5-74684879-T-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 NM_001292004.2(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 NM_001292004.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.22

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]

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_001292004.2	c.-376-4449T>G		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.-376-4449T>G		intron_variant	Intron 1 of 13	1		ENSP00000426285.1
ENSG00000306131	ENST00000815555.1	n.112+119A>C		intron_variant	Intron 1 of 1

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

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

Publications

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Other links and lift over

dbSNP: rs2593642; hg19: chr5-73980704;