rs730882196

Variant names:

• chr5-151259837-C-T
• rs730882196
• NM_000405.5:c.164C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-151259837-C-T
• chr5-151259837-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000405.5(GM2A):​c.164C>T​(p.Pro55Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,566 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GM2A NM_000405.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:3 U:2
• Conservation: PhyloP100: 7.50
• Publications: 9 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

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.164C>T	p.Pro55Leu	missense	Exon 2 of 4	NP_000396.2
	GM2A	NM_001167607.3		c.164C>T	p.Pro55Leu	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.164C>T	p.Pro55Leu	missense	Exon 2 of 4	ENSP00000349687.3	P17900
	GM2A	ENST00000523004.1	TSL:1	c.38C>T	p.Pro13Leu	missense	Exon 1 of 2	ENSP00000430541.1	H0YBY3
	GM2A	ENST00000523466.5	TSL:3	c.209C>T	p.Pro70Leu	missense	Exon 3 of 4	ENSP00000429100.1	E5RJD0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460566 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726684

African (AFR) AF: 0.0000299 AC: 1 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110822

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	2	-	Tay-Sachs disease, variant AB (4)
1	-	-	Neurodegenerative illness progressing to crippling dystonia and death with relentless cerebral atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.5
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-9.9	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.58		Loss of disorder (P = 0.0475)
MVP		0.91
MPC		0.41
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		-0.014	Neutral
Varity_R		0.96
gMVP		0.94
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs730882196; hg19: chr5-150639398; COSMIC: COSV64095824;