rs587779406

Positions:

chr15-72346552-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PM2PP5_Very_StrongBP4BP7

The NM_000520.6(HEXA):c.1305C>T(p.Tyr435=) 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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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/exons	MANE	Protein
HEXA	NM_000520.6 linkuse as main transcript	c.1305C>T	p.Tyr435=	synonymous_variant	11/14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2 linkuse as main transcript	c.1338C>T	p.Tyr446=	synonymous_variant	11/14		NP_001305754.1
HEXA	NR_134869.3 linkuse as main transcript	n.1116-227C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 linkuse as main transcript	c.1305C>T	p.Tyr435=	synonymous_variant	11/14	1	NM_000520.6	ENSP00000268097	P1	P06865-1
	ENST00000570175.1 linkuse as main transcript	n.1332G>A		non_coding_transcript_exon_variant	2/3	1

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

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251370

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135882

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 SAS 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

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

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

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	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%). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	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. -
Pathogenic, no assertion criteria provided	research	Unidad de Diagnostico y Tratamiento de Errores Congenitos del Metabolismo. Hospital Clínico Universitário de Santiago de Compostela	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 08, 2014	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 24, 2021	Variant summary: HEXA c.1305C>T alters a conserved nucleotide resulting in a synonymous change. Computational tools predict a significant impact on normal splicing, particularly that the variant disrupts/abolishes an exonic splicing enhancer site. Experimental evidence supports these predictions demonstrating the variant leads to complete absence of the normal transcript and formation of aberrant transcripts (Levit_2010). The variant allele was found at a frequency of 8e-05 in 251370 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (8e-05 vs 0.0014), allowing no conclusion about variant significance. c.1305C>T has been reported in the literature in compound heterozygous individuals affected with Tay-Sachs Disease (e.g. Levit_2010, Gort_2012, Fernandez-Marmiesse_2014, Georgiou_2014). These data indicate that the variant is likely to be associated with disease. One of the affected compound heterozygous individuals was noted with severe Hex A deficiency in the range known for patients suffering from TSD (4-10% Hex A). However, the enzymatic activity of the variant protein expressed in TSD glial cell-line as measured with 4-MUG as a substrate, was similar to that of wild-type (Levit_2010). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2024

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jun 21, 2021

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

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2024

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

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