chr15-72375972-T-C

Position:

• chr15-72375972-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The ENST00000268097.10(HEXA):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,076 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 0.0000066 (0 hom., cov: 32)
• Consequence: HEXA ENST00000268097.10 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 1.42

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000268097.10 (HEXA) was described as [Pathogenic] in ClinVar as 496858
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-72375972-T-C is Pathogenic according to our data. Variant chr15-72375972-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXA	NM_000520.6	c.1A>G	p.Met1?	start_lost	1/14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.1A>G	p.Met1?	start_lost	1/14		NP_001305754.1
HEXA	NR_134869.3	n.43A>G		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.1A>G	p.Met1?	start_lost	1/14	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.1A>G		non_coding_transcript_exon_variant	1/16	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.00000801 AC: 2 AN: 249732 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135252

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74296

Gnomad4 AFR AF: 0.0000242

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: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jan 02, 2020	This sequence change affects the initiator methionine of the HEXA mRNA. While it is expected to result in an absent or disrupted protein product, alternate methionines downstream of the initiator codon could potentially rescue the translation initiation; the next in-frame methionine is located at codon 193. This variant has been previously reported as a homozygous change in two brothers with infantile Tay-Sachs disease (PMID: 21796138) and as a compound heterozygous change in affected individuals (PMID: 1532289, 18358410). ClinVar contains an entry for this variant (Variation ID: 3914). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (2/249732) and thus is presumed to be rare. Based on the available evidence, the c.1A>G (p.Met1?) variant is classified as Pathogenic. -
Affects, no assertion criteria provided	literature only	OMIM	Apr 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 22, 2021	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3914). Disruption of the initiator codon has been observed in individual(s) with HEXA deficiency (PMID: 1532289, 21796138). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121907965, gnomAD 0.007%). This sequence change affects the initiator methionine of the HEXA mRNA. The next in-frame methionine is located at codon 193. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2023	Variant summary: HEXA c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The variant allele was found at a frequency of 8e-06 in 249732 control chromosomes. c.1A>G has been reported in the literature in individuals affected with Tay-Sachs Disease. These data indicate that the variant is likely to be associated with disease. Three 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. In addition, other variants affecting initiation codon (e.g. c.1A>C, c.1A>T, c.2T>C) have been reported to be pathogenic (HGMD, ClinVar). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.49
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.0032
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationTaster	Benign	1.0	A;A;A;A
PROVEAN	Benign	-0.49	N;N;N;.
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Uncertain	0.057	T;T;T;D
Polyphen		0.063	B;.;.;.
Vest4		0.78
MVP		0.97
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.96
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121907965; hg19: chr15-72668313;