chr15-72344096-T-G

Position:

• chr15-72344096-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000520.6(HEXA):​c.1571A>C​(p.Gln524Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HEXA NM_000520.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25811166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXA	NM_000520.6	c.1571A>C	p.Gln524Pro	missense_variant	14/14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.1604A>C	p.Gln535Pro	missense_variant	14/14		NP_001305754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.1571A>C	p.Gln524Pro	missense_variant	14/14	1	NM_000520.6	ENSP00000268097	P1
	ENST00000570175.1	n.166-1290T>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tay-Sachs disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 06, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with HEXA-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with proline at codon 524 of the HEXA protein (p.Gln524Pro). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.096
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.54
Sift	Benign	0.045	D;D
Sift4G	Benign	0.16	T;T
Polyphen		0.24	B;.
Vest4		0.21
MutPred		0.43		Loss of helix (P = 0.0237);.;
MVP		0.93
MPC		0.32
ClinPred		0.93	D
GERP RS		3.5
Varity_R		0.73
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-72636437;