5-74685086-G-C

Variant names:

• chr5-74685086-G-C
• rs73117116
• ENST00000511181.5:c.-376-4242G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000815555.1(ENSG00000306131):​n.24C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000198 in 505,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: ENSG00000306131 ENST00000815555.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• Publications: 0 publications found

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]

HEXB Gene-Disease associations (from GenCC):

• Sandhoff disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen, Genomics England PanelApp, Myriad Women’s Health

ENSG00000306131 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_001292004.2	c.-376-4242G>C		intron_variant	Intron 1 of 13		NP_001278933.1
HEXB	NM_000521.4	c.-175G>C		upstream_gene_variant		ENST00000261416.12	NP_000512.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12	c.-175G>C		upstream_gene_variant		1	NM_000521.4	ENSP00000261416.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000198 AC: 1 AN: 505174 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 262720

African (AFR) AF: 0.00 AC: 0 AN: 9882

American (AMR) AF: 0.00 AC: 0 AN: 11374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12556

East Asian (EAS) AF: 0.00 AC: 0 AN: 25778

South Asian (SAS) AF: 0.00 AC: 0 AN: 41254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2048

European-Non Finnish (NFE) AF: 0.00000289 AC: 1 AN: 345896

Other (OTH) AF: 0.00 AC: 0 AN: 27044

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.4
DANN	Benign	0.38
PhyloP100		1.0
PromoterAI		-0.060	Neutral

Splicing

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

Other links and lift over

dbSNP: rs73117116; hg19: chr5-73980911;