5-151253271-G-T

Variant names:

• chr5-151253271-G-T
• rs1048719
• NM_000405.5:c.55G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000405.5(GM2A):​c.55G>T​(p.Ala19Ser) 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 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A19T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GM2A NM_000405.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.100
• Publications: 18 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052018344).

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.55G>T	p.Ala19Ser	missense	Exon 1 of 4	NP_000396.2
	GM2A	NM_001167607.3		c.55G>T	p.Ala19Ser	missense	Exon 1 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.55G>T	p.Ala19Ser	missense	Exon 1 of 4	ENSP00000349687.3	P17900
	GM2A	ENST00000937902.1		c.55G>T	p.Ala19Ser	missense	Exon 1 of 3	ENSP00000607961.1
	GM2A	ENST00000523466.5	TSL:3	c.127-6484G>T		intron	N/A	ENSP00000429100.1	E5RJD0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 490

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.0
DANN	Benign	0.91
DEOGEN2	Benign	0.085	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.10
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.025
Sift	Benign	0.16	T
Sift4G	Benign	0.56	T
Polyphen		0.017	B
Vest4		0.075
MutPred		0.33		Gain of loop (P = 0.0097)
MVP		0.34
MPC		0.063
ClinPred		0.12	T
GERP RS		0.34
PromoterAI		-0.086	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.41
Mutation Taster		=94/6	polymorphism

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: rs1048719; hg19: chr5-150632832;