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GeneBe

5-151267375-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000405.5(GM2A):c.506G>C(p.Arg169Pro) variant causes a missense change. 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GM2A
NM_000405.5 missense

Scores

9
7
3

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.15
Variant links:
Genes affected
GM2A (HGNC:4367): (ganglioside GM2 activator) This gene encodes a small glycolipid transport protein which acts as a substrate specific co-factor for the lysosomal enzyme beta-hexosaminidase A. Beta-hexosaminidase A, together with GM2 ganglioside activator, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene result in GM2-gangliosidosis type AB or the AB variant of Tay-Sachs disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a chain Ganglioside GM2 activator isoform short (size 159) in uniprot entity SAP3_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_000405.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 5-151267375-G-C is Pathogenic according to our data. Variant chr5-151267375-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 391.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GM2ANM_000405.5 linkuse as main transcriptc.506G>C p.Arg169Pro missense_variant 4/4 ENST00000357164.4
GM2ANM_001167607.3 linkuse as main transcriptc.413-117G>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GM2AENST00000357164.4 linkuse as main transcriptc.506G>C p.Arg169Pro missense_variant 4/41 NM_000405.5 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Tay-Sachs disease, variant AB Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 1993- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
Cadd
Uncertain
25
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
D
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.71
T
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.19
D
MutationAssessor
Pathogenic
3.1
M
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.37
T
PROVEAN
Pathogenic
-5.8
D
REVEL
Pathogenic
0.73
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.024
D
Polyphen
1.0
D
Vest4
0.86
MutPred
0.83
Loss of sheet (P = 0.0315);
MVP
0.87
MPC
0.48
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.99
gMVP
0.95

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104893892; hg19: chr5-150646936; API