Genetic Variant HEXD:p.Ile145Val (chr17-82433808-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001330542.2(HEXD):c.433A>G(p.Ile145Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,611,518 control chromosomes in the GnomAD database, including 126,366 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 15296 hom., cov: 33)

Exomes 𝑓: 0.37 ( 111070 hom. )

Consequence

HEXD
NM_001330542.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0800

Publications

43 publications found

Variant links:

Genes affected

HEXD (HGNC:26307): (hexosaminidase D) Enables beta-N-acetylhexosaminidase activity. Predicted to be involved in carbohydrate metabolic process. Located in extracellular vesicle. [provided by Alliance of Genome Resources, Apr 2022]

HEXD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=4.8481857E-6).

BP6

Variant 17-82433808-A-G is Benign according to our data. Variant chr17-82433808-A-G is described in ClinVar as Benign. ClinVar VariationId is 402933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXD	NM_001330542.2 link	c.433A>G	p.Ile145Val	missense_variant	Exon 5 of 13	ENST00000327949.15	NP_001317471.1	Q8WVB3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXD	ENST00000327949.15 link	c.433A>G	p.Ile145Val	missense_variant	Exon 5 of 13	1	NM_001330542.2	ENSP00000332634.9		Q8WVB3-1

Frequencies

GnomAD3 genomes

AF:

0.428

AC:

65123

AN:

152064

Hom.:

15255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.495

Gnomad AMI

AF:

0.453

Gnomad AMR

AF:

0.564

Gnomad ASJ

AF:

0.384

Gnomad EAS

AF:

0.909

Gnomad SAS

AF:

0.440

Gnomad FIN

AF:

0.326

Gnomad MID

AF:

0.411

Gnomad NFE

AF:

0.337

Gnomad OTH

AF:

0.454

GnomAD2 exomes

AF:

0.450

AC:

110502

AN:

245678

AF XY:

0.434

show subpopulations

Gnomad AFR exome

AF:

0.499

Gnomad AMR exome

AF:

0.679

Gnomad ASJ exome

AF:

0.383

Gnomad EAS exome

AF:

0.915

Gnomad FIN exome

AF:

0.320

Gnomad NFE exome

AF:

0.336

Gnomad OTH exome

AF:

0.421

GnomAD4 exome

AF:

0.372

AC:

542627

AN:

1459336

Hom.:

111070

Cov.:

AF XY:

0.371

AC XY:

269402

AN XY:

725982

show subpopulations

African (AFR)

AF:

0.503

AC:

16781

AN:

33358

American (AMR)

AF:

0.662

AC:

29491

AN:

44522

Ashkenazi Jewish (ASJ)

AF:

0.381

AC:

9950

AN:

26086

East Asian (EAS)

AF:

0.914

AC:

36155

AN:

39554

South Asian (SAS)

AF:

0.430

AC:

37028

AN:

86016

European-Finnish (FIN)

AF:

0.328

AC:

17275

AN:

52720

Middle Eastern (MID)

AF:

0.364

AC:

2096

AN:

5758

European-Non Finnish (NFE)

AF:

0.333

AC:

369764

AN:

1110996

Other (OTH)

AF:

0.399

AC:

24087

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

16268

32537

48805

65074

81342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12284

24568

36852

49136

61420

<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:

0.429

AC:

65216

AN:

152182

Hom.:

15296

Cov.:

AF XY:

0.433

AC XY:

32186

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.496

AC:

20596

AN:

41534

American (AMR)

AF:

0.565

AC:

8634

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.384

AC:

1331

AN:

3468

East Asian (EAS)

AF:

0.909

AC:

4703

AN:

5174

South Asian (SAS)

AF:

0.438

AC:

2117

AN:

4828

European-Finnish (FIN)

AF:

0.326

AC:

3455

AN:

10600

Middle Eastern (MID)

AF:

0.401

AC:

118

AN:

294

European-Non Finnish (NFE)

AF:

0.337

AC:

22879

AN:

67974

Other (OTH)

AF:

0.459

AC:

971

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1857

3713

5570

7426

9283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

582

1164

1746

2328

2910

<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:

0.382

Hom.:

34978

Bravo

AF:

0.455

TwinsUK

AF:

0.326

AC:

1209

ALSPAC

AF:

0.330

AC:

1271

ESP6500AA

AF:

0.474

AC:

1839

ESP6500EA

AF:

0.338

AC:

2796

ExAC

AF:

0.438

AC:

52917

Asia WGS

AF:

0.658

AC:

2285

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.24

CADD

Benign

0.13

(source)

DANN

Benign

0.38

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.62

T;.;T;T;T

MetaRNN

Benign

0.0000048

T;T;T;T;T

MetaSVM

Benign

-0.96

PhyloP100

0.080

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.65

N;N;.;.;.

REVEL

Uncertain

0.33

Sift

Benign

0.28

T;T;.;.;.

Sift4G

Benign

0.35

T;T;T;T;.

Vest4

0.18

MPC

0.23

ClinPred

0.0032

GERP RS

0.036

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.38

Mutation Taster

=99/1

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over