rs16872141

Variant names:

• chr5-74643440-T-C
• rs16872141
• ENST00000511181.5:c.-377+2882T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000511181.5(HEXB):​c.-377+2882T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 152,212 control chromosomes in the GnomAD database, including 1,392 homozygotes. 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: 𝑓 0.13 (1392 hom., cov: 32)
• Consequence: HEXB ENST00000511181.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.704
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_001292004.2	c.-377+2882T>C		intron_variant	Intron 1 of 13		NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000511181.5	c.-377+2882T>C		intron_variant	Intron 1 of 13	1		ENSP00000426285.1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19506 AN: 152094 Hom.: 1386 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.0799

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0859

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.105

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.128 AC: 19531 AN: 152212 Hom.: 1392 Cov.: 32 AF XY: 0.128 AC XY: 9530 AN XY: 74416

African (AFR) AF: 0.178 AC: 7380 AN: 41488

American (AMR) AF: 0.0797 AC: 1219 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 271 AN: 3472

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5186

South Asian (SAS) AF: 0.0860 AC: 415 AN: 4826

European-Finnish (FIN) AF: 0.108 AC: 1142 AN: 10612

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8715 AN: 68022

Other (OTH) AF: 0.104 AC: 219 AN: 2110

Alfa AF: 0.139 Hom.: 413

Bravo AF: 0.126

Asia WGS AF: 0.0590 AC: 206 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.58
DANN	Benign	0.38
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs16872141; hg19: chr5-73939265; COSMIC: COSV56631190; COSMIC: COSV56631190;