chr5-151267451-A-T

Variant names:

• chr5-151267451-A-T
• rs1048723
• NM_000405.5:c.582A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_000405.5(GM2A):​c.582A>T​(p.Ter194Tyrext*?) variant causes a stop lost 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GM2A NM_000405.5 stop_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.644
• Publications: 19 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
• PM4: Stoplost variant in NM_000405.5 Downstream stopcodon found after 203 codons.

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.582A>T	p.Ter194Tyrext*?	stop_lost	Exon 4 of 4	NP_000396.2
	GM2A	NM_001167607.3		c.413-41A>T		intron	N/A	NP_001161079.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GM2A	ENST00000357164.4	TSL:1 MANE Select	c.582A>T	p.Ter194Tyrext*?	stop_lost	Exon 4 of 4	ENSP00000349687.3	P17900
	GM2A	ENST00000937902.1		c.420A>T	p.Ter140Tyrext*?	stop_lost	Exon 3 of 3	ENSP00000607961.1
	GM2A	ENST00000523004.1	TSL:1	c.*526A>T		downstream_gene	N/A	ENSP00000430541.1	H0YBY3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.8
DANN	Benign	0.49
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.13	N
PhyloP100		0.64
Vest4		0.011
GERP RS		-2.1
Mutation Taster		=103/97	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1048723; hg19: chr5-150647012;