NM_000405.5:c.205A>G

Variant names:

• chr5-151259878-A-G
• rs153478
• NM_000405.5:c.205A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000405.5(GM2A):​c.205A>G​(p.Met69Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 1,610,570 control chromosomes in the GnomAD database, including 397,237 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M69T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.75 (43324 hom., cov: 32)
  • Exomes 𝑓: 0.69 (353913 hom.)
• Consequence: GM2A NM_000405.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.762
• Publications: 37 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.680591E-7).
• BP6: Variant 5-151259878-A-G is Benign according to our data. Variant chr5-151259878-A-G is described in ClinVar as Benign. ClinVar VariationId is 167151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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.205A>G	p.Met69Val	missense	Exon 2 of 4	NP_000396.2
	GM2A	NM_001167607.3		c.205A>G	p.Met69Val	missense	Exon 2 of 4	NP_001161079.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GM2A	ENST00000357164.4	TSL:1 MANE Select	c.205A>G	p.Met69Val	missense	Exon 2 of 4	ENSP00000349687.3	P17900
	GM2A	ENST00000523004.1	TSL:1	c.79A>G	p.Met27Val	missense	Exon 1 of 2	ENSP00000430541.1	H0YBY3
	GM2A	ENST00000523466.5	TSL:3	c.250A>G	p.Met84Val	missense	Exon 3 of 4	ENSP00000429100.1	E5RJD0

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113456 AN: 151980 Hom.: 43271 Cov.: 32

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.749

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.921

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.744

GnomAD2 exomes AF: 0.760 AC: 190631 AN: 250874 AF XY: 0.760

Gnomad AFR exome AF: 0.860

Gnomad AMR exome AF: 0.850

Gnomad ASJ exome AF: 0.725

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.665

Gnomad NFE exome AF: 0.661

Gnomad OTH exome AF: 0.731

GnomAD4 exome AF: 0.690 AC: 1005802 AN: 1458472 Hom.: 353913 Cov.: 41 AF XY: 0.695 AC XY: 504642 AN XY: 725674

African (AFR) AF: 0.868 AC: 29038 AN: 33454

American (AMR) AF: 0.846 AC: 37803 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 18801 AN: 26122

East Asian (EAS) AF: 0.999 AC: 39659 AN: 39698

South Asian (SAS) AF: 0.911 AC: 78561 AN: 86220

European-Finnish (FIN) AF: 0.662 AC: 35341 AN: 53392

Middle Eastern (MID) AF: 0.792 AC: 4563 AN: 5760

European-Non Finnish (NFE) AF: 0.648 AC: 718352 AN: 1108868

Other (OTH) AF: 0.725 AC: 43684 AN: 60268

GnomAD4 genome AF: 0.747 AC: 113568 AN: 152098 Hom.: 43324 Cov.: 32 AF XY: 0.751 AC XY: 55831 AN XY: 74348

African (AFR) AF: 0.857 AC: 35583 AN: 41514

American (AMR) AF: 0.770 AC: 11763 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 2461 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5173 AN: 5178

South Asian (SAS) AF: 0.920 AC: 4437 AN: 4822

European-Finnish (FIN) AF: 0.654 AC: 6908 AN: 10566

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44753 AN: 67962

Other (OTH) AF: 0.747 AC: 1572 AN: 2104

Alfa AF: 0.703 Hom.: 81962

Bravo AF: 0.761

TwinsUK AF: 0.633 AC: 2349

ALSPAC AF: 0.644 AC: 2481

ESP6500AA AF: 0.851 AC: 3750

ESP6500EA AF: 0.657 AC: 5652

ExAC AF: 0.762 AC: 92523

Asia WGS AF: 0.949 AC: 3301 AN: 3478

EpiCase AF: 0.660

EpiControl AF: 0.670

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Tay-Sachs disease, variant AB (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.8
DANN	Benign	0.34
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.093	T
MetaRNN	Benign	7.7e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.90	N
PhyloP100		0.76
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.23
Sift	Benign	0.29	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.069
ClinPred		0.0095	T
GERP RS		-2.4
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.58
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs153478; hg19: chr5-150639439; COSMIC: COSV100852054;