chr5-74685420-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000261416.12(HEXB):c.160C>A(p.Pro54Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,600,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P54S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

HEXB
ENST00000261416.12 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:1

Conservation

PhyloP100: 0.283

Publications

0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen, Genomics England PanelApp, Myriad Women’s Health

HEXB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015567005).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261416.12. 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.160C>A	p.Pro54Thr	missense	Exon 1 of 14	NP_000512.2
	HEXB	NM_001292004.2		c.-376-3908C>A		intron	N/A	NP_001278933.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HEXB	ENST00000261416.12	TSL:1 MANE Select	c.160C>A	p.Pro54Thr	missense	Exon 1 of 14	ENSP00000261416.7
HEXB	ENST00000511181.5	TSL:1	c.-376-3908C>A		intron	N/A	ENSP00000426285.1
HEXB	ENST00000513079.5	TSL:2	n.225C>A		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151684

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000144

AC:

AN:

214966

AF XY:

0.000101

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000960

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:

0.0000228

AC:

AN:

1448956

Hom.:

Cov.:

AF XY:

0.0000180

AC XY:

AN XY:

720248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32944

American (AMR)

AF:

0.000764

AC:

AN:

43208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25870

East Asian (EAS)

AF:

0.00

AC:

AN:

38518

South Asian (SAS)

AF:

0.00

AC:

AN:

84992

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107510

Other (OTH)

AF:

0.00

AC:

AN:

59816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.00000659

AC:

AN:

151684

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74088

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41290

American (AMR)

AF:

0.0000656

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

4766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67898

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00135

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000100

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Sandhoff disease (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.23

CADD

Benign

6.5

(source)

DANN

Benign

0.85

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.051

M_CAP

Benign

0.083

MetaRNN

Benign

0.016

MetaSVM

Uncertain

-0.043

PhyloP100

0.28

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.54

REVEL

Benign

0.20

Sift

Benign

0.24

Sift4G

Benign

0.37

Vest4

0.099

MVP

0.76

MPC

0.30

ClinPred

0.031

GERP RS

2.2

PromoterAI

-0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.50

Mutation Taster

=95/5

polymorphism

(source)

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

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

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over