5-74685281-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000521.4(HEXB):c.21G>A(p.Gly7=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: HEXB NM_000521.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.349

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_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 5-74685281-G-A is Benign according to our data. Variant chr5-74685281-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2027089.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.349 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXB	NM_000521.4	c.21G>A	p.Gly7=	synonymous_variant	1/14	ENST00000261416.12
HEXB	NM_001292004.2	c.-376-4047G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXB	ENST00000261416.12	c.21G>A	p.Gly7=	synonymous_variant	1/14	1	NM_000521.4	P1
HEXB	ENST00000511181.5	c.-376-4047G>A		intron_variant		1
HEXB	ENST00000513079.5	n.86G>A		non_coding_transcript_exon_variant	1/6	2
HEXB	ENST00000515528.1	n.76G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1392832 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 688180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000271

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sandhoff disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	11
Dann	Benign	0.91
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1

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

Other links and lift over

dbSNP: rs771233421; hg19: chr5-73981106;