rs370266293

chr15-72346679-C-Gchr15-72346679-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000520.6(HEXA):c.1178G>C(p.Arg393Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R393Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: HEXA NM_000520.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.52

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 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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, 0.909
• PP5: Variant 15-72346679-C-G is Pathogenic according to our data. Variant chr15-72346679-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 218337.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.1178G>C	p.Arg393Pro	missense_variant	11/14	ENST00000268097.10
HEXA	NM_001318825.2	c.1211G>C	p.Arg404Pro	missense_variant	11/14
HEXA	NR_134869.3	n.1116-354G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.1178G>C	p.Arg393Pro	missense_variant	11/14	1	NM_000520.6	P1
	ENST00000570175.1	n.1459C>G		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tay-Sachs disease Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Oct 02, 2011

This variant found to be pathogenic by online software, including MutationTaster, Polyphen2 and SIFT. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.62	T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.4	M;.;.
MutationTaster	Benign	0.85	D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.87	P;.;.
Vest4		0.57
MutPred		0.69		Gain of catalytic residue at W392 (P = 0.1036);.;Gain of catalytic residue at W392 (P = 0.1036);
MVP		0.97
MPC		0.89
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.97
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs370266293; hg19: chr15-72639020;