rs72764638

Variant names:

• chr5-74715716-T-A
• rs72764638
• NM_000521.4:c.1082+26T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-74715716-T-A
• chr5-74715716-T-C

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.1082+26T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,200,260 control chromosomes in the GnomAD database, including 5,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2662 hom., cov: 30)
  • Exomes 𝑓: 0.11 (2720 hom.)
• Consequence: HEXB NM_000521.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.19
• Publications: 5 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=-0.81).
• BP6: Variant 5-74715716-T-A is Benign according to our data. Variant chr5-74715716-T-A is described in ClinVar as Benign. ClinVar VariationId is 256354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000521.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	NM_000521.4	MANE Select	c.1082+26T>A		intron	N/A	NP_000512.2
	HEXB	NM_001292004.2		c.407+26T>A		intron	N/A	NP_001278933.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	ENST00000261416.12	TSL:1 MANE Select	c.1082+26T>A		intron	N/A	ENSP00000261416.7
	HEXB	ENST00000511181.5	TSL:1	c.407+26T>A		intron	N/A	ENSP00000426285.1
	HEXB	ENST00000513336.5	TSL:3	c.104+26T>A		intron	N/A	ENSP00000423713.1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 24614 AN: 141834 Hom.: 2650 Cov.: 30

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.0575

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.190 AC: 28793 AN: 151712 AF XY: 0.182

Gnomad AFR exome AF: 0.330

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.237

Gnomad FIN exome AF: 0.0942

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.113 AC: 119290 AN: 1058352 Hom.: 2720 Cov.: 17 AF XY: 0.112 AC XY: 60320 AN XY: 540158

African (AFR) AF: 0.273 AC: 6788 AN: 24890

American (AMR) AF: 0.232 AC: 8886 AN: 38284

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2422 AN: 21866

East Asian (EAS) AF: 0.154 AC: 5270 AN: 34252

South Asian (SAS) AF: 0.117 AC: 8558 AN: 73380

European-Finnish (FIN) AF: 0.0580 AC: 2671 AN: 46066

Middle Eastern (MID) AF: 0.134 AC: 490 AN: 3660

European-Non Finnish (NFE) AF: 0.102 AC: 78384 AN: 770272

Other (OTH) AF: 0.127 AC: 5821 AN: 45682

GnomAD4 genome AF: 0.174 AC: 24662 AN: 141908 Hom.: 2662 Cov.: 30 AF XY: 0.173 AC XY: 11871 AN XY: 68748

African (AFR) AF: 0.302 AC: 11924 AN: 39456

American (AMR) AF: 0.225 AC: 3212 AN: 14300

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 370 AN: 3328

East Asian (EAS) AF: 0.178 AC: 879 AN: 4936

South Asian (SAS) AF: 0.143 AC: 636 AN: 4446

European-Finnish (FIN) AF: 0.0612 AC: 499 AN: 8156

Middle Eastern (MID) AF: 0.167 AC: 45 AN: 270

European-Non Finnish (NFE) AF: 0.105 AC: 6712 AN: 64180

Other (OTH) AF: 0.170 AC: 335 AN: 1966

Alfa AF: 0.135 Hom.: 228

Bravo AF: 0.186

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.73
PhyloP100		2.2
PromoterAI		-0.0081	Neutral
Mutation Taster		=8/92	disease causing (long InDel)

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: rs72764638; hg19: chr5-74011541; COSMIC: COSV54668660; COSMIC: COSV54668660;