Genetic Variant NM_000521.4:c.449C>A (chr5-74693642-C-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_000521.4(HEXB):c.449C>A(p.Thr150Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,609,124 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T150P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0090 ( 27 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 19 hom. )

Consequence

HEXB
NM_000521.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0700

Publications

6 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: Benign. The variant received -16 ACMG points.

PM1

In a chain Beta-hexosaminidase subunit beta chain B (size 189) in uniprot entity HEXB_HUMAN there are 15 pathogenic changes around while only 2 benign (88%) in NM_000521.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-74693641-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 554994.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047442913).

BP6

Variant 5-74693642-C-A is Benign according to our data. Variant chr5-74693642-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235583.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 = 0.00896 (1364/152260) while in subpopulation AFR AF = 0.0308 (1281/41540). AF 95% confidence interval is 0.0294. There are 27 homozygotes in GnomAd4. There are 622 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	NM_000521.4	MANE Select	c.449C>A	p.Thr150Asn	missense	Exon 3 of 14	NP_000512.2
	HEXB	NM_001292004.2		c.-227C>A		5_prime_UTR	Exon 3 of 14	NP_001278933.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HEXB	ENST00000261416.12	TSL:1 MANE Select	c.449C>A	p.Thr150Asn	missense	Exon 3 of 14	ENSP00000261416.7
HEXB	ENST00000511181.5	TSL:1	c.-227C>A		5_prime_UTR	Exon 3 of 14	ENSP00000426285.1
HEXB	ENST00000510820.1	TSL:3	n.168C>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.00895

AC:

1362

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0309

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00399

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:

0.000103

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00253

AC:

636

AN:

251488

AF XY:

0.00178

show subpopulations

Gnomad AFR exome

AF:

0.0344

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000958

AC:

1395

AN:

1456864

Hom.:

Cov.:

AF XY:

0.000786

AC XY:

570

AN XY:

725114

show subpopulations

African (AFR)

AF:

0.0307

AC:

1023

AN:

33374

American (AMR)

AF:

0.00174

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000151

AC:

167

AN:

1107422

Other (OTH)

AF:

0.00188

AC:

113

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

148

221

295

369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00896

AC:

1364

AN:

152260

Hom.:

Cov.:

AF XY:

0.00835

AC XY:

622

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0308

AC:

1281

AN:

41540

American (AMR)

AF:

0.00399

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68012

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

136

205

273

341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00336

Hom.:

Bravo

AF:

0.0105

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0318

AC:

140

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00306

AC:

372

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 26, 2015

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 13, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria.

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sandhoff disease

Benign:3

Jul 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

4.2

(source)

DANN

Benign

0.89

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.015

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.71

PhyloP100

-0.070

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.1

REVEL

Benign

0.17

Sift

Benign

0.16

Sift4G

Benign

0.35

Vest4

0.11

MVP

0.64

MPC

0.20

ClinPred

0.00088

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.49

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

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

Publications

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over