rs41271747

Variant names:

• chr5-74689282-T-A
• rs41271747
• NM_000521.4:c.300-46T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-74689282-T-A
• chr5-74689282-T-G

Variant summary

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

The NM_000521.4(HEXB):​c.300-46T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.093 in 1,504,790 control chromosomes in the GnomAD database, including 7,705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (505 hom., cov: 33)
  • Exomes 𝑓: 0.096 (7200 hom.)
• Consequence: HEXB NM_000521.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.258
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 5-74689282-T-A is Benign according to our data. Variant chr5-74689282-T-A is described in ClinVar as Benign. ClinVar VariationId is 256357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_000521.4	c.300-46T>A		intron_variant	Intron 1 of 13	ENST00000261416.12	NP_000512.2
HEXB	NM_001292004.2	c.-376-46T>A		intron_variant	Intron 1 of 13		NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12	c.300-46T>A		intron_variant	Intron 1 of 13	1	NM_000521.4	ENSP00000261416.7
HEXB	ENST00000511181.5	c.-376-46T>A		intron_variant	Intron 1 of 13	1		ENSP00000426285.1
HEXB	ENST00000513079.5	n.365-46T>A		intron_variant	Intron 1 of 5	2
HEXB	ENST00000515528.1	n.355-46T>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.0702 AC: 10684 AN: 152182 Hom.: 506 Cov.: 33

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.0892

Gnomad AMR AF: 0.0594

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0775

GnomAD2 exomes AF: 0.0720 AC: 17981 AN: 249768 AF XY: 0.0722

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0433

Gnomad ASJ exome AF: 0.0901

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0796

GnomAD4 exome AF: 0.0956 AC: 129276 AN: 1352490 Hom.: 7200 Cov.: 23 AF XY: 0.0934 AC XY: 63457 AN XY: 679456

African (AFR) AF: 0.0159 AC: 494 AN: 30994

American (AMR) AF: 0.0461 AC: 2054 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.0907 AC: 2316 AN: 25526

East Asian (EAS) AF: 0.0000765 AC: 3 AN: 39194

South Asian (SAS) AF: 0.0219 AC: 1838 AN: 83792

European-Finnish (FIN) AF: 0.0984 AC: 5160 AN: 52460

Middle Eastern (MID) AF: 0.0601 AC: 320 AN: 5322

European-Non Finnish (NFE) AF: 0.111 AC: 112037 AN: 1013838

Other (OTH) AF: 0.0890 AC: 5054 AN: 56800

GnomAD4 genome AF: 0.0702 AC: 10689 AN: 152300 Hom.: 505 Cov.: 33 AF XY: 0.0682 AC XY: 5079 AN XY: 74470

African (AFR) AF: 0.0187 AC: 779 AN: 41576

American (AMR) AF: 0.0595 AC: 909 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 290 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0246 AC: 119 AN: 4832

European-Finnish (FIN) AF: 0.103 AC: 1096 AN: 10604

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7237 AN: 68026

Other (OTH) AF: 0.0767 AC: 162 AN: 2112

Alfa AF: 0.0846 Hom.: 95

Bravo AF: 0.0659

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.9
DANN	Benign	0.75
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs41271747; hg19: chr5-73985107; COSMIC: COSV54668347; COSMIC: COSV54668347;