15-72345528-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000520.6(HEXA):c.1444G>A(p.Glu482Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,102 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: HEXA NM_000520.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.49

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000520.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 15-72345528-C-T is Pathogenic according to our data. Variant chr15-72345528-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72345528-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.1444G>A	p.Glu482Lys	missense_variant	13/14	ENST00000268097.10
HEXA	NM_001318825.2	c.1477G>A	p.Glu493Lys	missense_variant	13/14
HEXA	NR_134869.3	n.1229G>A		non_coding_transcript_exon_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.1444G>A	p.Glu482Lys	missense_variant	13/14	1	NM_000520.6	P1
	ENST00000570175.1	n.308C>T		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251424 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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: 0.00000752 AC: 11 AN: 1461862 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74374

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Pathogenic:4 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 05, 2023	Variant summary: HEXA c.1444G>A (p.Glu482Lys) results in a conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251424 control chromosomes. c.1444G>A has been reported in the literature as a homozygous genotype in multiple individuals affected with Tay-Sachs Disease and in settings of multigene panel testing for neurological disorders (example, Nakano_1988, Akli_1993 overlapping Poenaru_1994, Montalvo_2005, Ganapathy_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Dersh_2019). The most pronounced variant effect results in abolishment of enzymatic activity against MUGS substrate, unprocessed by lysosomal proteases and altered folding as compared to the wild-type enzyme. This study also demonstrated that this variant retrotranslocated from the endoplasmic reticulum (ER) to the cytosol and was degraded by the proteasome, indicating clearance via ER-associated degradation (ERAD). The following publications have been ascertained in the context of this evaluation (PMID: 8490625, 27682588, 31069529, 16088929, 2970528, 7858168). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Affects, no assertion criteria provided	literature only	OMIM	Aug 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 20, catalytic domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least two patients with Tay Sachs disease and has been classified as likely pathogenic by a diagnostic laboratory (ClinVar; PMID: 1301190, 2970528, 16088929). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Studies on patient fibroblasts demonstrated markedly reduced enzymatic activities and in vitro analysis demonstrated this is due to altered folding and inability to be secreted (PMID: 27682588). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 482 of the HEXA protein (p.Glu482Lys). This variant is present in population databases (rs121907952, gnomAD 0.006%). This missense change has been observed in individual(s) with hexosaminidase A deficiency (PMID: 1301190, 2970528, 9338583, 16088929). ClinVar contains an entry for this variant (Variation ID: 3892). 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%. Experimental studies have shown that this missense change affects HEXA function (PMID: 1301190, 8328462, 27682588). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2021

The c.1444G>A (p.E482K) alteration is located in exon 13 (coding exon 13) of the HEXA gene. This alteration results from a G to A substitution at nucleotide position 1444, causing the glutamic acid (E) at amino acid position 482 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (2/251424) total alleles studied. This alteration has been reported in patients with Tay-Sachs disease (Nakano, 1988; Montalvo, 2005). Based on internal structural analysis, this variant is highly destabilizing to the local structure (Novak, 1994; Hou, 1996; Hou, 1998; Hepbildikler, 2002; Lemieux, 2006). Enzymatic activity was undetectable in both cultured patient fibroblasts and cells transiently expressing p.E482K. In addition, p.E482K was severely misfolded and degraded by the proteosome (Brown, 1993; Dersh, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 08, 2022

PP3, PM2, PM3, PS3, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.99
MutPred		0.98		Gain of MoRF binding (P = 0.0081);.;Gain of MoRF binding (P = 0.0081);
MVP		1.0
MPC		0.79
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs121907952; hg19: chr15-72637869;