5-74685135-C-T

Variant names:

• chr5-74685135-C-T
• rs71627068
• ENST00000511181.5:c.-376-4193C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001292004.2(HEXB):​c.-376-4193C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 1,052,904 control chromosomes in the GnomAD database, including 169,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23248 hom., cov: 31)
  • Exomes 𝑓: 0.57 (146198 hom.)
• Consequence: HEXB NM_001292004.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.274

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 5-74685135-C-T is Benign according to our data. Variant chr5-74685135-C-T is described in ClinVar as [Benign]. Clinvar id is 369506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_001292004.2	c.-376-4193C>T		intron_variant	Intron 1 of 13		NP_001278933.1
HEXB	NM_000521.4	c.-126C>T		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.-126C>T		upstream_gene_variant		1	NM_000521.4	ENSP00000261416.7

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83239 AN: 151228 Hom.: 23230 Cov.: 31

Gnomad AFR AF: 0.558

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.552

GnomAD4 exome AF: 0.567 AC: 511065 AN: 901556 Hom.: 146198 Cov.: 12 AF XY: 0.566 AC XY: 253380 AN XY: 447706

African (AFR) AF: 0.559 AC: 9837 AN: 17598

American (AMR) AF: 0.377 AC: 4755 AN: 12606

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 8791 AN: 15200

East Asian (EAS) AF: 0.478 AC: 13163 AN: 27560

South Asian (SAS) AF: 0.568 AC: 28543 AN: 50242

European-Finnish (FIN) AF: 0.623 AC: 18377 AN: 29510

Middle Eastern (MID) AF: 0.590 AC: 1666 AN: 2826

European-Non Finnish (NFE) AF: 0.572 AC: 403650 AN: 706006

Other (OTH) AF: 0.557 AC: 22283 AN: 40008

GnomAD4 genome AF: 0.550 AC: 83292 AN: 151348 Hom.: 23248 Cov.: 31 AF XY: 0.549 AC XY: 40614 AN XY: 73918

African (AFR) AF: 0.558 AC: 23027 AN: 41260

American (AMR) AF: 0.412 AC: 6282 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 2001 AN: 3468

East Asian (EAS) AF: 0.461 AC: 2334 AN: 5066

South Asian (SAS) AF: 0.552 AC: 2650 AN: 4800

European-Finnish (FIN) AF: 0.622 AC: 6517 AN: 10474

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.572 AC: 38738 AN: 67726

Other (OTH) AF: 0.550 AC: 1160 AN: 2110

Alfa AF: 0.363 Hom.: 693

Bravo AF: 0.531

Asia WGS AF: 0.470 AC: 1634 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Uncertain	0.98
PhyloP100		-0.27
PromoterAI		-0.44	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: rs71627068; hg19: chr5-73980960;