Variant rs1057519467 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000520.6(HEXA):c.1432G>A(p.Gly478Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G478G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HEXA
NM_000520.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.56

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000520.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

PP5

Variant 15-72345540-C-T is Pathogenic according to our data. Variant chr15-72345540-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 375364.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-72345540-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HEXA	NM_000520.6 linkuse as main transcript	c.1432G>A	p.Gly478Arg	missense_variant	13/14	ENST00000268097.10
HEXA	NM_001318825.2 linkuse as main transcript	c.1465G>A	p.Gly489Arg	missense_variant	13/14
HEXA	NR_134869.3 linkuse as main transcript	n.1217G>A		non_coding_transcript_exon_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10 linkuse as main transcript	c.1432G>A	p.Gly478Arg	missense_variant	13/14	1	NM_000520.6	P1	P06865-1
	ENST00000570175.1 linkuse as main transcript	n.320C>T		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727230

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Mar 22, 2011

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.69

T;T;T

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.3

M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.2

N;N;N

REVEL

Pathogenic

0.80

Sift

Uncertain

0.012

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.95

P;.;.

Vest4

0.82

MutPred

0.84

Gain of methylation at G478 (P = 0.0108);.;Gain of methylation at G478 (P = 0.0108);

MVP

0.99

MPC

0.80

ClinPred

0.98

GERP RS

5.7

Varity_R

0.92

gMVP

0.95

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over