5-74721131-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000521.4(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
NM_000521.4 missense

Scores

8
7
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.04
Variant links:
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]
GFM2 (HGNC:29682): (GTP dependent ribosome recycling factor mitochondrial 2) Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors, which is a GTPase that plays a role at the termination of mitochondrial translation by mediating the disassembly of ribosomes from messenger RNA . Its role in the regulation of normal mitochondrial function and in disease states attributed to mitochondrial dysfunction is not known. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

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 rank MANE Protein UniProt
HEXBNM_000521.4 linkc.1627G>C p.Ala543Pro missense_variant Exon 14 of 14 ENST00000261416.12 NP_000512.2 P07686A0A024RAJ6
GFM2NM_032380.5 linkc.*524C>G downstream_gene_variant ENST00000296805.8 NP_115756.2 Q969S9-1A0A024RAK1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HEXBENST00000261416.12 linkc.1627G>C p.Ala543Pro missense_variant Exon 14 of 14 1 NM_000521.4 ENSP00000261416.7 P07686
GFM2ENST00000296805.8 linkc.*524C>G downstream_gene_variant 1 NM_032380.5 ENSP00000296805.3 Q969S9-1

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
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

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

Other links and lift over

dbSNP: rs121907984; hg19: chr5-74016956; API