rs77499935

Positions:

chr5-74718812-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000521.4(HEXB):c.1258A>G(p.Ile420Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,614,156 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 21 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 21 hom. )

Consequence

HEXB
NM_000521.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.750

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046886504).

BP6

Variant 5-74718812-A-G is Benign according to our data. Variant chr5-74718812-A-G is described in ClinVar as [Benign]. Clinvar id is 256355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00855 (1302/152314) while in subpopulation AFR AF= 0.0297 (1235/41568). AF 95% confidence interval is 0.0283. There are 21 homozygotes in gnomad4. There are 616 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXB	NM_000521.4 link	c.1258A>G	p.Ile420Val	missense_variant	11/14	ENST00000261416.12	NP_000512.2	P07686A0A024RAJ6
HEXB	NM_001292004.2 link	c.583A>G	p.Ile195Val	missense_variant	11/14		NP_001278933.1	P07686Q5URX0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12 link	c.1258A>G	p.Ile420Val	missense_variant	11/14	1	NM_000521.4	ENSP00000261416.7		P07686

Frequencies

GnomAD3 genomes

AF:

0.00854

AC:

1300

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0297

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00218

AC:

547

AN:

251412

Hom.:

AF XY:

0.00165

AC XY:

224

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.0300

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000900

AC:

1315

AN:

1461842

Hom.:

Cov.:

AF XY:

0.000762

AC XY:

554

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0323

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.00172

GnomAD4 genome

AF:

0.00855

AC:

1302

AN:

152314

Hom.:

Cov.:

AF XY:

0.00827

AC XY:

616

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0297

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00184

Hom.:

Bravo

AF:

0.00932

ESP6500AA

AF:

0.0266

AC:

117

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00280

AC:

340

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sandhoff disease

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Feb 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.25

CADD

Benign

1.5

DANN

Benign

0.74

DEOGEN2

Uncertain

0.48

T;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.83

T;.

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.24

PROVEAN

Benign

0.22

N;N

REVEL

Uncertain

0.33

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.15

MVP

0.52

MPC

0.15

ClinPred

0.00084

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over