15-72345476-C-T

Position:

• chr15-72345476-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000520.6(HEXA):​c.1496G>A​(p.Arg499His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: HEXA NM_000520.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 7.56

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]

ENSG00000260729 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 15-72345476-C-T is Pathogenic according to our data. Variant chr15-72345476-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72345476-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXA	NM_000520.6	c.1496G>A	p.Arg499His	missense_variant	13/14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.1529G>A	p.Arg510His	missense_variant	13/14		NP_001305754.1
HEXA	NR_134869.3	n.1281G>A		non_coding_transcript_exon_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.1496G>A	p.Arg499His	missense_variant	13/14	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.578G>A		non_coding_transcript_exon_variant	5/16	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152234 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251458 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000718 AC: 105 AN: 1461850 Hom.: 0 Cov.: 35 AF XY: 0.0000784 AC XY: 57 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152234 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74372

Gnomad4 AFR AF: 0.0000241

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000574 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003899). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 14577003 , 29214523). A different missense change at the same codon (p.Arg499Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003915). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 21, 2020	A heterozygous missense variation in exon 13 of the HEXA gene that results in the amino acid substitution of Histidine for Arginine at codon 499 was detected. The observed variant c.1496G>A (p.Arg499His) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is possibly damaging by PolyPhen-2 (HumDiv) and damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jan 02, 2020	This variant has been reported in the literature in the compound heterozygote state in individuals affected with infantile Tay-Sachs disease and in individuals with the juvenile onset form (PMID 29214523, 31367523, 18490185, 2144098). ClinVar contains an entry for this variant (Variation ID: 3899). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (14/251458) and thus is presumed to be rare. The c.1496G>A (p.Arg499His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1496G>A (p.Arg499His) variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 17, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2018	Variant summary: HEXA c.1496G>A (p.Arg499His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant, c.1496G>A, was observed with an allele frequency of 5.7e-05 in 246362 control chromosomes (gnomAD and publication controls). This frequency is not significantly higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (5.7e-05 vs 0.0014), allowing no conclusion about variant significance. The variant, c.1496G>A, has been reported in the literature in multiple compound heterozygote individuals affected with Tay-Sachs Disease, while some present with a subacute phenotype or late-onset (adult and juvenile). Multiple clinical diagnostic laboratories via ClinVar submissions (evaluations performed after 2014) classify the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 499 of the HEXA protein (p.Arg499His). This variant is present in population databases (rs121907956, gnomAD 0.03%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 2144098, 14577003, 17237499). ClinVar contains an entry for this variant (Variation ID: 3899). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HEXA protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 14, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2024	Published functional studies demonstrate a damaging effect (retention of the Hex alpha-subunit in the ER and posterior degradation along with a lower value of the solvent-accessible surface area) (PMID: 2140574); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26984043, 1833974, 2140574, 18490185, 29214523, 22441121, 35936646, 34288098, 33240792, 17237499, 34302356, 24767253, 31367523, 19091716) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	HEXA: PP4:Strong, PM2, PM3, PM5 -

Gm2-gangliosidosis, juvenile Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2003

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2021

The c.1496G>A (p.R499H) alteration is located in coding exon 13 of the HEXA gene. This alteration results from a G to A substitution at nucleotide position 1496, causing the arginine (R) at amino acid position 499 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (14/251458) total alleles studied. The highest observed frequency was 0.03% (10/30614) of South Asian alleles. This alteration has been reported in multiple individuals with Tay-Sachs disease with a second HEXA alteration (Paw, 1990; Maegawa, 2006; Stepien, 2018; Ou, 2019). This amino acid position is highly conserved in available vertebrate species. The p.R499H amino acid is located in the GH20_HexA_HexB-like domain. Biosynthetic studies of the R499H alteration revealed the synthesis of an abnormal a-subunit which did not associate with the b-subunit. It was not processed into the mature lysosomal form and appeared to be retained and degraded in the endoplasmic reticulum, possibly due to misfolding. However some residual enzyme activity (~3%) was observed (Paw, 1990). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.98
MVP		0.99
MPC		0.84
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs121907956; hg19: chr15-72637817;