Genetic Variant NM_000405.5:c.37C>G (chr5-151253253-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000405.5(GM2A):c.37C>G(p.Leu13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L13L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GM2A
NM_000405.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.124

Publications

0 publications found

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]

GM2A Gene-Disease associations (from GenCC):

Tay-Sachs disease AB variant
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

GM2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24685085).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000405.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GM2A	NM_000405.5	MANE Select	c.37C>G	p.Leu13Val	missense	Exon 1 of 4	NP_000396.2
	GM2A	NM_001167607.3		c.37C>G	p.Leu13Val	missense	Exon 1 of 4	NP_001161079.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GM2A	ENST00000357164.4	TSL:1 MANE Select	c.37C>G	p.Leu13Val	missense	Exon 1 of 4	ENSP00000349687.3	P17900
GM2A	ENST00000937902.1		c.37C>G	p.Leu13Val	missense	Exon 1 of 3	ENSP00000607961.1
GM2A	ENST00000523466.5	TSL:3	c.127-6502C>G		intron	N/A	ENSP00000429100.1	E5RJD0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727194

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111926

Other (OTH)

AF:

0.00

AC:

AN:

60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.14

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.45

M_CAP

Benign

0.012

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.72

MutationAssessor

Benign

2.0

PhyloP100

0.12

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.77

REVEL

Benign

0.071

Sift

Benign

0.065

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.16

MutPred

0.32

Gain of catalytic residue at L13 (P = 0.0489)

MVP

0.51

MPC

0.068

ClinPred

0.79

GERP RS

0.29

PromoterAI

0.0088

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.087

gMVP

0.58

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over