rs70976124

Variant names:

• chr5-74685138-GC-G
• rs70976124
• ENST00000511181.5:c.-376-4189delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001292004.2(HEXB):​c.-376-4189delC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23250 hom., cov: 0)
  • Exomes 𝑓: 0.56 (151750 hom.)
• Consequence: HEXB NM_001292004.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00
• Publications: 6 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 -16 ACMG points.

• BP6: Variant 5-74685138-GC-G is Benign according to our data. Variant chr5-74685138-GC-G is described in ClinVar as Benign. ClinVar VariationId is 369507.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292004.2. 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.-376-4189delC		intron	N/A	NP_001278933.1	Q5URX0
	HEXB	NM_000521.4	MANE Select	c.-122delC		upstream_gene	N/A	NP_000512.2	P07686

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	ENST00000511181.5	TSL:1	c.-376-4189delC		intron	N/A	ENSP00000426285.1	Q5URX0
	HEXB	ENST00000261416.12	TSL:1 MANE Select	c.-122delC		upstream_gene	N/A	ENSP00000261416.7	P07686
	HEXB	ENST00000513079.5	TSL:2	n.-57delC		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83244 AN: 151264 Hom.: 23232 Cov.: 0

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: 0.551

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.552

GnomAD4 exome AF: 0.563 AC: 530677 AN: 943042 Hom.: 151750 Cov.: 0 AF XY: 0.562 AC XY: 262327 AN XY: 466632

African (AFR) AF: 0.557 AC: 10268 AN: 18428

American (AMR) AF: 0.375 AC: 4893 AN: 13048

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 8919 AN: 15464

East Asian (EAS) AF: 0.477 AC: 13272 AN: 27838

South Asian (SAS) AF: 0.566 AC: 29121 AN: 51448

European-Finnish (FIN) AF: 0.623 AC: 18391 AN: 29542

Middle Eastern (MID) AF: 0.588 AC: 1700 AN: 2890

European-Non Finnish (NFE) AF: 0.567 AC: 421089 AN: 742828

Other (OTH) AF: 0.554 AC: 23024 AN: 41556

GnomAD4 genome AF: 0.550 AC: 83297 AN: 151384 Hom.: 23250 Cov.: 0 AF XY: 0.549 AC XY: 40611 AN XY: 73934

African (AFR) AF: 0.558 AC: 23034 AN: 41274

American (AMR) AF: 0.412 AC: 6285 AN: 15256

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

East Asian (EAS) AF: 0.461 AC: 2332 AN: 5064

South Asian (SAS) AF: 0.552 AC: 2648 AN: 4798

European-Finnish (FIN) AF: 0.622 AC: 6512 AN: 10472

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

European-Non Finnish (NFE) AF: 0.572 AC: 38742 AN: 67748

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

Alfa AF: 0.275 Hom.: 693

Asia WGS AF: 0.471 AC: 1634 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Sandhoff disease (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
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: rs70976124; hg19: chr5-73980963;