rs587779406

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BP7

The NM_000520.6(HEXA):c.1305C>T(p.Tyr435Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

HEXA
NM_000520.6 synonymous

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 3.49

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:

ENSG00000261460 (HGNC:58304):

ENSG00000261460 links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PP5

Variant 15-72346552-G-A is Pathogenic according to our data. Variant chr15-72346552-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 100729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72346552-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.23). . Strength limited to SUPPORTING due to the PP5.

BP7

Synonymous conserved (PhyloP=3.49 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6 link	c.1305C>T	p.Tyr435Tyr	synonymous_variant	Exon 11 of 14	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.1338C>T	p.Tyr446Tyr	synonymous_variant	Exon 11 of 14		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.1116-227C>T		intron_variant	Intron 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.1305C>T	p.Tyr435Tyr	synonymous_variant	Exon 11 of 14	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.413-227C>T		intron_variant	Intron 3 of 15	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000796

AC:

AN:

251370

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.000425

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26134

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39698

Gnomad4 SAS exome

AF:

0.0000348

AC:

AN:

86252

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53418

Gnomad4 NFE exome

AF:

0.00000270

AC:

AN:

1111920

Gnomad4 Remaining exome

AF:

0.0000331

AC:

AN:

60388

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.000362

AC:

0.000361934

AN:

0.000361934

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000158

Hom.:

Bravo

AF:

0.0000793

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:6

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This synonymous variant affects a weakly conserved nucleotide in exon 11 of 14 and is predicted to affect an exonic splicing enhancer site. Functional evidence suggests this variant may lead to exon 11 skipping and is likely to interfere with normal splicing (PMID: 20363167). This variant has been previously reported as a compound heterozygous change in patients with juvenile Tay-Sachs disease, Tay-Sachs disease, and juvenile type 2 gangliosidosis (PMID 24767253, 20363167, 22789865, 25606403). The c.1305C>T (p.Tyr435=) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.008% (24/282766) and is absent in the homozygous state. Based on the available evidence, the c.1305C>T (p.Tyr435=) variant is classified as Likely Pathogenic. -

Oct 08, 2014

Counsyl

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Sep 16, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 435 of the HEXA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the HEXA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587779406, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with juvenile Tay-Sachs disease (PMID: 20363167, 22789865, 24767253, 25606403). 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: 100729). Studies have shown that this variant results in skipping of exons 9-12 and introduces a premature termination codon (PMID: 20363167). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Apr 18, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HEXA c.1305C>T (p.Tyr435=) alters a conserved nucleotide resulting in a synonymous change. Computational tools predict a significant impact on normal splicing, particularly that the variant affects exonic splicing enhancer/silencer site(s), resulting in a higher chance of exon skipping than the WT allele. Experimental evidence supports these predictions, demonstrating that the variant leads to complete absence of the normal transcript and formation of aberrant transcripts (Levit_2010). The variant, c.1305C>T, was found at a frequency of 4e-05 in 1606950 control chromosomes (gnomAD v4.1). GnomAD also indicates that this variant is part of a multinucleotide variation (MNV), comprising of c.1305C>T and c.1306A>G (p.Ile436Val). The neighboring single nucleotide variant (SNV), c.1306A>G (p.Ile436Val), was found at a population frequency of 0.96 (gnomAD), suggesting that it is the major allele. Examination of the IGV read data in the gnomAD database supports that the two variants tend to occur together in the same reads, i.e. as an MNV. Based on these results, it can be estimated that the c.1305C>T variant in isolation will be found at a frequency not to exceed 4e-05. This frequency is not higher than the maximum expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (0.0014), allowing no conclusion about variant significance. The variant, c.1305C>T (p.Tyr435=), has been reported in the literature in individuals affected with the juvenile form Tay-Sachs Disease and related phenotypes (e.g. Levit_2010, Gort_2012, Fernandez-Marmiesse_2014, Georgiou_2014, Martinez-Rubio_2022). Since these papers didn't specify the sequence context for the variant, it is unclear whether some of the reported patients could carry the MNV (i.e. c.1305_1306delinsTG), and this could not be confirmed with the authors at time of classification. The c.1306A>G (p.Ile436Val) in isolation has been reported as benign among several submitters in the ClinVar database (ClinVar ID 93189). The following publications have been ascertained in the context of this evaluation (PMID: 24767253, 25606403, 22789865, 20363167, 36233161). ClinVar contains an entry for this variant (Variation ID: 100729). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Unidad de Diagnostico y Tratamiento de Errores Congenitos del Metabolismo. Hospital Clínico Universitário de Santiago de Compostela

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Inborn genetic diseases

Pathogenic:1

Jun 05, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1305C>T (p.Y435Y) alteration is located in coding exon 11 of the HEXA gene. This alteration consists of a C to T substitution at nucleotide position 1305. This nucleotide substitution does not change the amino acid at codon 435. However, further evidence has suggested this nucleotide change is deleterious. Based on data from gnomAD, the T allele has an overall frequency of 0.009% (24/282766) total alleles studied. The highest observed frequency was 0.048% (17/35436) of Latino alleles. This alteration was detected in conjunction with another alteration in HEXA, in multiple individuals with Tay-Sachs disease (Gort, 2012; Fernandez-Marmiesse, 2014; Georgiou, 2014). This nucleotide position is well conserved in available vertebrate species. In an assay testing HEXA function, this variant showed a functionally abnormal result (Levit, 2010). In silico splice site analysis for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Leukodystrophy;C0036572:Seizure;C1384666:Hearing impairment

Pathogenic:1

Jun 21, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 moderate -

not provided

Pathogenic:1

Apr 05, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20363167, 25606403, 22789865) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=78/22

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

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