ENST00000511181.5:c.-376-4449T>G

Variant names:

• chr5-74684879-T-G
• rs2593642
• ENST00000511181.5:c.-376-4449T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000511181.5(HEXB):​c.-376-4449T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 151,382 control chromosomes in the GnomAD database, including 21,510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.53 (21510 hom., cov: 30)
• Consequence: HEXB ENST00000511181.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.22
• 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: Genomics England PanelApp, Myriad Women’s Health, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ENSG00000306131 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 5-74684879-T-G is Benign according to our data. Variant chr5-74684879-T-G is described in ClinVar as Benign. ClinVar VariationId is 680595.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000511181.5. 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.-376-4449T>G		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.-376-4449T>G		intron	N/A	ENSP00000426285.1	Q5URX0
	ENSG00000306131	ENST00000815555.1		n.112+119A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.528 AC: 79872 AN: 151266 Hom.: 21497 Cov.: 30

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.535

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

GnomAD4 genome AF: 0.528 AC: 79904 AN: 151382 Hom.: 21510 Cov.: 30 AF XY: 0.528 AC XY: 39037 AN XY: 73932

African (AFR) AF: 0.479 AC: 19765 AN: 41248

American (AMR) AF: 0.404 AC: 6164 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 1997 AN: 3460

East Asian (EAS) AF: 0.459 AC: 2348 AN: 5118

South Asian (SAS) AF: 0.553 AC: 2651 AN: 4794

European-Finnish (FIN) AF: 0.622 AC: 6506 AN: 10464

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.572 AC: 38769 AN: 67742

Other (OTH) AF: 0.533 AC: 1120 AN: 2102

Alfa AF: 0.537 Hom.: 2609

Bravo AF: 0.507

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.2
DANN	Benign	0.43
PhyloP100		-1.2
PromoterAI		-0.028	Neutral
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: rs2593642; hg19: chr5-73980704;