Variant 15-72344093-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000520.6(HEXA):c.1574A>G(p.Glu525Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

HEXA
NM_000520.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.73

Variant links:

Genes affected

HEXA (HGNC:4878): (hexosaminidase subunit alpha) This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

HEXA links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXA	NM_000520.6 linkuse as main transcript	c.1574A>G	p.Glu525Gly	missense_variant	14/14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2 linkuse as main transcript	c.1607A>G	p.Glu536Gly	missense_variant	14/14		NP_001305754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 linkuse as main transcript	c.1574A>G	p.Glu525Gly	missense_variant	14/14	1	NM_000520.6	ENSP00000268097	P1	P06865-1
	ENST00000570175.1 linkuse as main transcript	n.166-1293T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461640

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Tay-Sachs disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 09, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 525 of the HEXA protein (p.Glu525Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HEXA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

T;T

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.41

MutPred

0.34

Loss of disorder (P = 0.1041);.;

MVP

1.0

MPC

0.79

ClinPred

1.0

GERP RS

5.8

Varity_R

0.78

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.27

Position offset: 47

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over