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rs387906309

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:29U:1O:1

Conservation

PhyloP100: 0.774
Variant links:
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]

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ACMG classification

Classification made for transcript

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
HEXANM_000520.6 linkuse as main transcriptc.1277_1278insTATC p.Tyr427IlefsTer5 frameshift_variant 11/14 ENST00000268097.10
HEXANM_001318825.2 linkuse as main transcriptc.1310_1311insTATC p.Tyr438IlefsTer5 frameshift_variant 11/14
HEXANR_134869.3 linkuse as main transcriptn.1116-255_1116-254insTATC intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HEXAENST00000268097.10 linkuse as main transcriptc.1277_1278insTATC p.Tyr427IlefsTer5 frameshift_variant 11/141 NM_000520.6 P1P06865-1
ENST00000570175.1 linkuse as main transcriptn.1360_1363dup non_coding_transcript_exon_variant 2/31

Frequencies

GnomAD3 genomes
AF:
0.000440
AC:
67
AN:
152154
Hom.:
0
Cov.:
30
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:29Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Tay-Sachs disease Pathogenic:21Other:1
Affects, no assertion criteria providedliterature onlyOMIMMar 01, 2004- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Oct 18, 2019NM_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, no assertion criteria providedcurationReproductive Health Research and Development, BGI GenomicsJan 06, 2020NM_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 -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaAug 29, 2018The 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 submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMar 31, 2022Based 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 18, 2017The 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 21, 2017Variant 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 submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversitySep 26, 2015The 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 submitterclinical testingInvitaeJan 28, 2024This 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 submitterclinical testingMGZ Medical Genetics CenterDec 03, 2021- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital BonnMar 29, 2023- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 18, 2021- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 02, 2024Criteria applied: PVS1,PM3_VSTR,PM2_SUP -
Pathogenic, no assertion criteria providedresearchFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsSep 11, 2014- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Mar 17, 2017- -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyJul 10, 2014- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 15, 2014- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenNov 08, 2017- -
Pathogenic, criteria provided, single submitterclinical testingDaryl Scott Lab, Baylor College of MedicineAug 22, 2022- -
Pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterJun 07, 2021- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMay 27, 2022- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University Hospital MuensterMay 30, 2022ACMG categories: PVS1,PS4,PP5,BS1 -
not provided Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJun 04, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 31, 2020Common 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, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2022HEXA: PVS1, PM2, PM3 -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 13, 2015- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 27, 2021The 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 submitterclinical testingCentogene AG - the Rare Disease Company-- -
Intellectual disability Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de LilleJan 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs387906309; hg19: chr15-72638920; API