5-74674772-C-T

Variant names:

• chr5-74674772-C-T
• rs820841
• ENST00000511181.5:c.-376-14556C>T

Variant summary

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

The NM_001292004.2(HEXB):​c.-376-14556C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 151,786 control chromosomes in the GnomAD database, including 16,337 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 0.44 (16337 hom., cov: 31)
• Consequence: HEXB NM_001292004.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.389
• Publications: 7 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: Genomics England PanelApp, Myriad Women’s Health, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.545 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292004.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	NM_001292004.2		c.-376-14556C>T		intron	N/A	NP_001278933.1	Q5URX0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	ENST00000511181.5	TSL:1	c.-376-14556C>T		intron	N/A	ENSP00000426285.1	Q5URX0

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67353 AN: 151668 Hom.: 16334 Cov.: 31

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.467

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

GnomAD4 genome AF: 0.444 AC: 67350 AN: 151786 Hom.: 16337 Cov.: 31 AF XY: 0.443 AC XY: 32885 AN XY: 74154

African (AFR) AF: 0.252 AC: 10425 AN: 41382

American (AMR) AF: 0.369 AC: 5629 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1882 AN: 3466

East Asian (EAS) AF: 0.422 AC: 2171 AN: 5150

South Asian (SAS) AF: 0.491 AC: 2351 AN: 4788

European-Finnish (FIN) AF: 0.572 AC: 6010 AN: 10514

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.550 AC: 37334 AN: 67922

Other (OTH) AF: 0.465 AC: 983 AN: 2112

Alfa AF: 0.514 Hom.: 88633

Bravo AF: 0.418

Asia WGS AF: 0.394 AC: 1372 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.78
DANN	Benign	0.71
PhyloP100		-0.39
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: rs820841; hg19: chr5-73970597;