rs121907977

chr15-72349163-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000520.6(HEXA):c.902T>G(p.Met301Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,758 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M301L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: HEXA NM_000520.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 9.21

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a disulfide_bond (size 51) in uniprot entity HEXA_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_000520.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 15-72349163-A-C is Pathogenic according to our data. Variant chr15-72349163-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3933.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.902T>G	p.Met301Arg	missense_variant	8/14	ENST00000268097.10
HEXA	NM_001318825.2	c.935T>G	p.Met312Arg	missense_variant	8/14
HEXA	NR_134869.3	n.944T>G		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.902T>G	p.Met301Arg	missense_variant	8/14	1	NM_000520.6	P1
	ENST00000570175.1	n.1578-1061A>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251438 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461500 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727104

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: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74402

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tay-Sachs disease Pathogenic:3 Uncertain:1 Other:1

Likely 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 8 of the HEXA gene that results in the amino acid substitution of Arginine for Methionine at codon 301 was detected. The observed variant c.902T>G (p.Met301Arg) 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 likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 30, 2022	- -
Affects, no assertion criteria provided	literature only	OMIM	Jan 01, 1993	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2023	Variant summary: HEXA c.902T>G (p.Met301Arg) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251438 control chromosomes. c.902T>G has been reported in the literature in homozygous and compound heterozygous individuals affected with Tay-Sachs Disease (Akil_1993, Cheema_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8490625, 33083013). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as Pathogenic (n=1), Likely Pathogenic (n=1) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 28, 2023	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 301 of the HEXA protein (p.Met301Arg). This variant is present in population databases (rs121907977, gnomAD 0.01%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 8490625, 33083013). ClinVar contains an entry for this variant (Variation ID: 3933). 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. For these reasons, this variant has been classified as Pathogenic. -

Tay-Sachs disease;C0268275:Tay-Sachs disease, variant AB Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	26
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.97	D;.;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.97	D;.;.
Vest4		0.97
MutPred		0.91		Gain of catalytic residue at M301 (P = 0.0631);.;Gain of catalytic residue at M301 (P = 0.0631);
MVP		0.99
MPC		0.93
ClinPred		0.97	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.99

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: rs121907977; hg19: chr15-72641504;