5-74721131-G-C

Position:

• chr5-74721131-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The ENST00000261416.12(HEXB):​c.1627G>C​(p.Ala543Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. A543T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HEXB ENST00000261416.12 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.04

Genes affected

HEXB (HGNC:4879): (hexosaminidase subunit beta) Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000261416.12
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXB	NM_000521.4	c.1627G>C	p.Ala543Pro	missense_variant	14/14	ENST00000261416.12	NP_000512.2
HEXB	NM_001292004.2	c.952G>C	p.Ala318Pro	missense_variant	14/14		NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12	c.1627G>C	p.Ala543Pro	missense_variant	14/14	1	NM_000521.4	ENSP00000261416	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.34	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Vest4		0.89
MutPred		0.68		.;Loss of MoRF binding (P = 0.0682);.;
MVP		0.98
MPC		0.82
ClinPred		1.0	D
GERP RS		6.0
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs121907984; hg19: chr5-74016956;