rs17561000

Variant names:

• chr5-74713502-A-G
• rs17561000
• NM_000521.4:c.772-4A>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.772-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0834 in 1,607,770 control chromosomes in the GnomAD database, including 6,249 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (430 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5819 hom.)
• Consequence: HEXB NM_000521.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003431
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.791
• Publications: 17 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 5-74713502-A-G is Benign according to our data. Variant chr5-74713502-A-G is described in ClinVar as Benign. ClinVar VariationId is 93203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.093 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	NM_000521.4	MANE Select	c.772-4A>G		splice_region intron	N/A	NP_000512.2	P07686
	HEXB	NM_001292004.2		c.97-4A>G		splice_region intron	N/A	NP_001278933.1	Q5URX0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	ENST00000261416.12	TSL:1 MANE Select	c.772-4A>G		splice_region intron	N/A	ENSP00000261416.7	P07686
	HEXB	ENST00000511181.5	TSL:1	c.97-4A>G		splice_region intron	N/A	ENSP00000426285.1	Q5URX0
	HEXB	ENST00000504459.5	TSL:3	n.-36A>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0672 AC: 10228 AN: 152128 Hom.: 430 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0538

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0504

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0950

Gnomad OTH AF: 0.0750

GnomAD2 exomes AF: 0.0722 AC: 18139 AN: 251386 AF XY: 0.0745

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.0399

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0946

Gnomad OTH exome AF: 0.0794

GnomAD4 exome AF: 0.0851 AC: 123929 AN: 1455524 Hom.: 5819 Cov.: 29 AF XY: 0.0848 AC XY: 61402 AN XY: 724472

African (AFR) AF: 0.0136 AC: 455 AN: 33400

American (AMR) AF: 0.0409 AC: 1827 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3097 AN: 26074

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39654

South Asian (SAS) AF: 0.0531 AC: 4572 AN: 86148

European-Finnish (FIN) AF: 0.113 AC: 6039 AN: 53386

Middle Eastern (MID) AF: 0.0590 AC: 340 AN: 5758

European-Non Finnish (NFE) AF: 0.0929 AC: 102784 AN: 1106206

Other (OTH) AF: 0.0798 AC: 4805 AN: 60178

GnomAD4 genome AF: 0.0672 AC: 10230 AN: 152246 Hom.: 430 Cov.: 32 AF XY: 0.0676 AC XY: 5033 AN XY: 74458

African (AFR) AF: 0.0166 AC: 688 AN: 41564

American (AMR) AF: 0.0538 AC: 823 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 413 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0512 AC: 247 AN: 4820

European-Finnish (FIN) AF: 0.125 AC: 1323 AN: 10594

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0950 AC: 6459 AN: 68012

Other (OTH) AF: 0.0747 AC: 158 AN: 2114

Alfa AF: 0.0849 Hom.: 1335

Bravo AF: 0.0596

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0991

EpiControl AF: 0.0936

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	Sandhoff disease (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.5
DANN	Benign	0.57
PhyloP100		0.79
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.0		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: rs17561000; hg19: chr5-74009327;