chr15-72348047-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000520.6(HEXA):c.1073+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000604 in 1,602,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 0 hom. )

Consequence

HEXA
NM_000520.6 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22O:1

Conservation

PhyloP100: 7.34

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]

HEXA links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

ENSG00000261460 (HGNC:58304):

ENSG00000261460 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.054716982 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.4, offset of 17, new splice context is: aggGTgggt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-72348047-C-T is Pathogenic according to our data. Variant chr15-72348047-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72348047-C-T is described in Lovd as [Pathogenic]. Variant chr15-72348047-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6 link	c.1073+1G>A	splice_donor_variant, intron_variant	Intron 9 of 13	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.1106+1G>A	splice_donor_variant, intron_variant	Intron 9 of 13		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.1115+1G>A	splice_donor_variant, intron_variant	Intron 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.1073+1G>A		splice_donor_variant, intron_variant	Intron 9 of 13	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.413-1722G>A		intron_variant	Intron 3 of 15	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

251210

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000644

AC:

934

AN:

1450438

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

437

AN XY:

722324

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000817

Gnomad4 OTH exome

AF:

0.000433

GnomAD4 genome

AF:

0.000223

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000385

Hom.:

Bravo

AF:

0.000283

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:14

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR analysis on patient fibroblasts showed this variant has multiple aberrant splicing outcomes (PMID: 1301938). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (57 heterozygotes, 0 homozygotes). (SP) 0703 - Other splice site variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two other canonical splice site variants, c.1073+1G>C and c.1073+1G>T, have been reported in ClinVar as pathogenic and likely pathogenic respectively. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in individuals with Tay-Sachs disease (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 -

Nov 12, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000520.4(HEXA):c.1073+1G>A(aka IVS9+1G>A) is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that the c.1073+1G>A variant is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 8444467, 1387685, 22789865, 17015493, 8490625, 1837283 and 1301938. Classification of NM_000520.4(HEXA):c.1073+1G>A(aka IVS9+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

Dec 29, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The HEXA c.1073+1G>A variant involves the alteration of a highly conserved nucleotide in the canonical splice donor site in intron 9. This variant was found in 27/119996 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0003776 (25/66208). This frequency is about lower the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). This variant is a known common pathogenic variant mainly found in non-Jewish Caucasian (Landels_1992, Landels_1993, McDowell_1992, Akli_1993, Gort_2012, Utz_2015) with consistent genotype-phenotype and functional data. The frequency in control population therefore represents the carrier frequency. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -

Mar 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 10, 2014

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 17, 2014

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 30, 2015

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found twice in our laboratory in trans with another pathogenic variant: in a 25-year-old female [with c.820-7G>A] with motor delay, hypotonia, scoliosis, progressive weakness, mild ankle contractures, mildly diminished sensation, gait abnormalities, sister possibly similarly symptomatic (not tested); in a 1-year-old male [with Y427fs] with IUGR, severe delays with regression, hypotonia, epilepsy, microcephaly, FTT, polymicrogyria, absent HEXA activity. Variant pathogenic in recessive state; heterozygotes are carriers. -

Oct 26, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Aug 22, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HEXA c.1073+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.1073+1G>A variant affects a splice donor site in intron 9 and has been primarily reported in non-Ashkenazi Jewish probands of European descent (Park et al. 2010). Across a selection of available literature, the c.1073+1G>A variant has been identified in a homozygous state in three probands, in a compound heterozygous state in eight probands, in a heterozygous state in five probands in whom a second variant was not identified, and in seven probands in whom zygosity is unknown (Landels et al. 1992; McDowell et al. 1992; Akli et al. 1992; Akerman et al. 1992; Landels et al. 1993; Gort et al. 2012). The c.1073+1G>A variant was also identified in a heterozygous state in 25 unaffected carriers. The c.1073+1G>A variant was absent from 56 control alleles and is reported at a frequency of 0.000388 in the European (non-Finnish) population of the Genome Aggregation Database. RT-PCR analysis demonstrated that the c.1073+1G>A variant disrupts splicing of the HEXA gene and results in the production of numerous abnormal mRNA products (Akerman et al. 1992). Based on the evidence, the c.1073+1G>A variant is classified as pathogenic for hexoaminidase A deficiency. -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 9 of the HEXA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is present in population databases (rs76173977, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 1387685, 8490625, 19858779, 33426165). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3920). 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. -

not provided

Pathogenic:6Other:1

MutSpliceDB: a database of splice sites variants effects on splicing, NIH

Significance: not provided

Review Status: no classification provided

Collection Method: research

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2012

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HEXA: PVS1, PM2, PM3 -

Jun 12, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HEXA c.1073+1G>A variant disrupts a canonical splice-donor site and interferes with normal HEXA mRNA splicing (PMIDs: 1301938 (1992), 1387685 (1992)). In the published literature, this variant has been reported in individuals/families affected with the classic, infantile form of Tay-Sachs disease (also known as GM2 gangliosidosis) (PMIDs: 1307230 (1992), 8444467 (1993)) and with a late-onset form of the disease (LOTS) (PMIDs: 31076878 (2019), 33426165 (2021)). The frequency of this variant in the general population, 0.00059 (30/50744 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Jan 20, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified on approximately 17% of alleles from non-Jewish Caucasians with Tay-Sachs disease and is associated with infantile onset (Akerman et al., 1992); Canonical splice site variant predicted to result in an in-frame deletion of exon 9; Published functional studies demonstrate c.1073+1 G>A destroys the canonical splice donor site in intron 9, activates a cryptic donor site, and causes abnormal gene splicing (Akerman et al., 1992; Akli et al., 1993); This variant is associated with the following publications: (PMID: 22344438, 25525159, 22975760, 28476546, 29152458, 1837283, 29930972, 21228398, 8444467, 26874567, 29352662, 26633545, 1387685, 1301938, 17237499, 31076878, 31980526, 33426165, 25900722, 8326491) -

Aug 27, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM2_moderate, PM3_very_strong, PVS1_moderate -

HEXA-related disorder

Pathogenic:1

Jun 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HEXA c.1073+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also described as IVS9+1G>A, has been documented as causative for Tay-Sachs disease (Akli et al. 1991. PubMed ID: 1837283; Park et al. 2010. PubMed ID: 19858779). This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Nov 06, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1073+1G>A intronic pathogenic mutation (also known as IVS9+1G>A) results from a G to A substitution one nucleotide after coding exon 9 of the HEXA gene. This mutation is one of the most common found outside the Ashkenazi Jewish population, resulting in the activation of a cryptic donor site and abnormal RNA with a 17-bp insertion, which in turn leads to a reading frame shift and premature truncation (Akli S et al. Hum Genet. 1993;90(6):614-620). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.93

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.53

Position offset: -16

DS_DL_spliceai

0.93

Position offset: 1

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over