ENST00000511181.5:c.-376-4189C>A

Variant names:

• chr5-74685139-C-A
• rs1438020226
• ENST00000511181.5:c.-376-4189C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000511181.5(HEXB):​c.-376-4189C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. 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: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HEXB ENST00000511181.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_001292004.2	c.-376-4189C>A		intron_variant	Intron 1 of 13		NP_001278933.1
HEXB	NM_000521.4	c.-122C>A		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.-122C>A		upstream_gene_variant		1	NM_000521.4	ENSP00000261416.7

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 179724 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 89118

African (AFR) AF: 0.00 AC: 0 AN: 3668

American (AMR) AF: 0.00 AC: 0 AN: 5096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2764

East Asian (EAS) AF: 0.00 AC: 0 AN: 7634

South Asian (SAS) AF: 0.00 AC: 0 AN: 9872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 498

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 137724

Other (OTH) AF: 0.00 AC: 0 AN: 8200

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		0.0
PromoterAI		-0.13	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1438020226; hg19: chr5-73980964;