rs5030731

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3PP3PP5_Very_Strong

The NM_000521.4(HEXB):c.1082+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000837 in 1,552,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000458186: "In vitro functional studies demonstrated that the c.1082+5G>A variant produces a shorter transcript that lacks exon 8, and this leads to a frameshift and the generation of a premature stop codon." PMID:22722242" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

HEXB
NM_000521.4 splice_region, intron

Scores

Splicing: ADA: 0.9996

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.29

Publications

5 publications found

Variant links:

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

HEXB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000458186: "In vitro functional studies demonstrated that the c.1082+5G>A variant produces a shorter transcript that lacks exon 8, and this leads to a frameshift and the generation of a premature stop codon." PMID:22722242; SCV000629382: Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22848519).; SCV002548066: This has been experimentally validated via a minigene splicing assay, which reported the variant caused loss of 178 nucleotides in exon 8, resulting in a frameshift (p.G301_W361delfsX10, Zampieri_2012).

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 5-74715695-G-A is Pathogenic according to our data. Variant chr5-74715695-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 354135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1082+5G>A		splice_region intron	N/A	NP_000512.2	P07686
	HEXB	NM_001292004.2		c.407+5G>A		splice_region intron	N/A	NP_001278933.1	Q5URX0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HEXB	ENST00000261416.12	TSL:1 MANE Select	c.1082+5G>A	splice_region intron	N/A	ENSP00000261416.7	P07686
HEXB	ENST00000511181.5	TSL:1	c.407+5G>A	splice_region intron	N/A	ENSP00000426285.1	Q5URX0
HEXB	ENST00000513336.5	TSL:3	c.104+5G>A	splice_region intron	N/A	ENSP00000423713.1	H0Y9B6

Frequencies

GnomAD3 genomes

AF:

0.0000465

AC:

AN:

150398

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000399

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250056

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000428

AC:

AN:

1402330

Hom.:

Cov.:

AF XY:

0.00000428

AC XY:

AN XY:

700702

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32026

American (AMR)

AF:

0.0000225

AC:

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25710

East Asian (EAS)

AF:

0.00

AC:

AN:

39260

South Asian (SAS)

AF:

0.00

AC:

AN:

84980

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53104

Middle Eastern (MID)

AF:

0.000578

AC:

AN:

5190

European-Non Finnish (NFE)

AF:

0.00000189

AC:

AN:

1059282

Other (OTH)

AF:

0.00

AC:

AN:

58246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000465

AC:

AN:

150398

Hom.:

Cov.:

AF XY:

0.0000818

AC XY:

AN XY:

73350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40764

American (AMR)

AF:

0.000399

AC:

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10172

Middle Eastern (MID)

AF:

0.00321

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67762

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Sandhoff disease (7)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

PhyloP100

6.3

PromoterAI

-0.0087

Neutral

(source)

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.65

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.46

Position offset: -9

DS_DL_spliceai

0.65

Position offset: -5

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over