rs387906309

chr15-72346579-G-GGATA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000520.6(HEXA):c.1277_1278insTATC(p.Tyr427IlefsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000538 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S426S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: HEXA NM_000520.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:30 U:1 O:1
• Conservation: PhyloP100: 0.774

Genes affected

HEXA (HGNC:4878): (hexosaminidase subunit alpha) This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-72346579-G-GGATA is Pathogenic according to our data. Variant chr15-72346579-G-GGATA is described in ClinVar as [Pathogenic]. Clinvar id is 3889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.1277_1278insTATC	p.Tyr427IlefsTer5	frameshift_variant	11/14	ENST00000268097.10
HEXA	NM_001318825.2	c.1310_1311insTATC	p.Tyr438IlefsTer5	frameshift_variant	11/14
HEXA	NR_134869.3	n.1116-255_1116-254insTATC		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.1277_1278insTATC	p.Tyr427IlefsTer5	frameshift_variant	11/14	1	NM_000520.6	P1
	ENST00000570175.1	n.1360_1363dup		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152154 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000803 AC: 202 AN: 251460 Hom.: 0 AF XY: 0.000699 AC XY: 95 AN XY: 135910

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000548 AC: 801 AN: 1461798 Hom.: 0 Cov.: 34 AF XY: 0.000535 AC XY: 389 AN XY: 727208

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.000374

Gnomad4 NFE exome AF: 0.000324

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152154 Hom.: 0 Cov.: 30 AF XY: 0.000390 AC XY: 29 AN XY: 74318

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.000582

EpiCase AF: 0.000709

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Pathogenic:22 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tay-Sachs disease (MIM#272800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (210 heterozygotes, 0 homozygotes). (I) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the most common variants to cause Tay-Sachs disease in the Ashkenazi Jewish population (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Aug 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift c.1274_1277dup p.Tyr427IlefsTer5 variant in HEXA gene has been previously reported in homozygous and compound heterozygous states in multiple individuals affected with GM2 gangliosidoses Scott et al., 2010; Zampieri et al., 2012; Jamali et al., 2014. The p.Tyr427IlefsTer5 variant has been reported with allele frequency of 0.07% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. This variant causes a frameshift starting with codon Tyrosine 427, changes this amino acid to Isoleucine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Tyr427IlefsTer5. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Sep 11, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2017	Variant summary: This c.1274_1277dupTATC (p.Tyr427Ilefs) results in a premature termination codon, predicted to cause a truncated or absent HEXA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One functional study found less than 5% b-Hexosaminidase activity in leukocytes from a patient with Tay-Sachs disease carrying this variant in compound heterozygosity with p.R510H (not in our internal database)(Udwadia-Hedge_2017). This variant was found in the large control database ExAC in 92/121426 control chromosomes at a frequency of 0.0007577, which does not exceed the maximal expected frequency of a pathogenic allele (0.0013975) in this gene. This variant has been reported as a common pathogenic variant found especially in Ashkenazi Jews population with consistent clinical and genetic data (Myerowitz_1988, Jamali_2014, Zampieri_2012). Multiple clinical labs as well as reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 26, 2015	The c.1274_1277dupTATC, (p.Tyr427Ilefs*5) is a known frameshift variant that has been shown to result in the absence of mRNA. To that effect, the majority of pathogenic variants in the Ashkenazi Jewish TSD are null alleles, making it a common mechanism of disease. Moreover, this 4 basepair insertion variant has been reported in the majority of affected individuals of Ashkenazi Jewish ancestry (Myerowitz and Costigan, 1988), and has not been seen in the normal population databases (1000 Genomes, ExAc, and Exome Sequencing Project [ESP]). In summary, this variant is best classified as a recessive pathogenic variant for Tay-Sachs disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Mar 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 29, 2018	The HEXA c.1274_1277dupTATC (p.Tyr427IlefsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Tyr427IlefsTer5 variant has been identified in eight probands in a homozygous state, two probands in a compound heterozygous state and in five probands with unknown zygosity (Myerowitz et al. 1988; McDowell et al. 1992; Jamali et al. 2014; Sheth et al. 2014). The c.1274_1277dupTATC (p.Tyr427IlefsTer5) the most common HEXA variant in the Ashkenazi Jewish population and accounts for approximately 80% of variant HEXA alleles in this population (Kaback et al. 2011). Segregation of the variant with the disease has been shown in at least two families (Myerowitz et al. 1988). The variant was found in 69 of 2238 controls in a heterozygous state and is reported at a frequency of 0.00157 in the European American population of the Exome Sequencing Project. Due to the potential impact of frameshift variants, the p.Tyr427IlefsTer5 variant is classified as pathogenic for hexosaminidase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jul 10, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000520.4(HEXA):c.1274_1277dupTATC(Y427Ifs*5) is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that the Y427Ifs*5 variant is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 2848800, 1307230, 1830584, 11463833, and 14727180. Classification of NM_000520.4(HEXA):c.1274_1277dupTATC(Y427Ifs*5) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Tyr427Ilefs*5) in the HEXA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is present in population databases (rs387906309, gnomAD 1.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with Tay-Sachs disease (PMID: 2848800, 16352452, 20301397, 24518553, 25287655). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 2848800, 22975760). This variant is also known as c.1277_1278insTATC. ClinVar contains an entry for this variant (Variation ID: 3889). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2017	The p.Tyr427IlefsX5 (NM_000520.4 c.1274_1277dupTATC) variant in HEXA is a common pathogenic variant that has been reported in many compound heterozygous and hom ozygous individuals with Tay-Sachs disease (Myerowitz 1988, Montalvo 2005, Scott 2010, Gort 2012, Zampieri 2012, Jamail 2014). It has been reported in ClinVar ( Variation ID#3889) as pathogenic by multiple laboratories. This variant has been identified in 1.3% (135/10152) of Ashkenazi Jewish chromosomes and 0.03% (48/12 6682) of European chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs387906309). Although this variant has been s een in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 427 and le ads to a premature termination codon 5 amino acids downstream. This alteration i s then predicted to lead to a truncated or absent protein. Biallelic loss of fun ction in the HEXA gene is an established disease mechanism for Tay-Sachs disease . In summary, this variant meets criteria to be classified as pathogenic for Ta y-Sachs disease in an autosomal recessive manner based upon a predicted null eff ect and its biallelic occurrence in individuals with this disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 02, 2024	Criteria applied: PVS1,PM3_VSTR,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 08, 2017	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000520.4:c.1274_1277dupTATC in the HEXA gene has an allele frequency of 0.013 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is located at the 11th exon (14 exons in the NM_000520.4 transcript), therefore, it is predicted to lead nonsense-mediated mRNA decay. The c.1274_1277dupTATC (p.Tyr427Ilefs*5) variant has been reported multiple times and is determiend as the most common disease-causing variant in the Ashkenazi Jewis (PMID: 20672374). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PS4; PP4 -
Affects, no assertion criteria provided	literature only	OMIM	Mar 01, 2004	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	May 30, 2022	ACMG categories: PVS1,PS4,PP5,BS1 -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 07, 2021	- -

not provided Pathogenic:6

Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2020	Common pathogenic variant in the HEXA gene found in the Ashkenazi Jewish population and associated with infantile onset Tay-Sachs disease (Kaback, M., 2011); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31980526, 31076878, 30548430, 28333917, 29352662, 27959697, 21228398, 28503624, 1307230, 2848800, 27033294, 8352284, 2294750, 1830584, 8488832, 14727180, 25287655, 22975760, 30609409) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	HEXA: PVS1, PM2, PM3 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2021

The c.1274_1277dupTATC (p.Y427Ifs*5) alteration, located in coding exon 11 of the HEXA gene, consists of a duplication of TATC at position 1274, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.07% (210/282850) total alleles studied. The highest observed frequency was 1.29% (134/10370) of Ashkenazi Jewish alleles. This mutation is the most common Tay-Sachs disease alteration found in the Ashkenazi Jewish population (Myerowitz, 1988) and has been shown to account for approximately 80% of all mutant HEXA Ashkenazi Jewish alleles (Kaback, 1993; Scott, 2010). Based on the available evidence, this alteration is classified as pathogenic. -

Tay-Sachs disease;C0268275:Tay-Sachs disease, variant AB Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

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Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906309; hg19: chr15-72638920;