dbSNP rs35097575: EXD3:p.Thr533Met (chr9-137349428-G-A) – 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_017820.5(EXD3):c.1598C>T(p.Thr533Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,600,154 control chromosomes in the GnomAD database, including 2,088 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 161 hom., cov: 32)

Exomes 𝑓: 0.049 ( 1927 hom. )

Consequence

EXD3
NM_017820.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.96

Publications

10 publications found

Variant links:

Genes affected

EXD3 (HGNC:26023): (exonuclease 3'-5' domain containing 3) Predicted to enable 3'-5' exonuclease activity. Predicted to be involved in nucleic acid phosphodiester bond hydrolysis. [provided by Alliance of Genome Resources, Apr 2022]

EXD3 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=0.0020832121).

BP6

Variant 9-137349428-G-A is Benign according to our data. Variant chr9-137349428-G-A is described in ClinVar as Benign. ClinVar VariationId is 402840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXD3	NM_017820.5 link	c.1598C>T	p.Thr533Met	missense_variant	Exon 15 of 22	ENST00000340951.9	NP_060290.3	Q8N9H8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXD3	ENST00000340951.9 link	c.1598C>T	p.Thr533Met	missense_variant	Exon 15 of 22	1	NM_017820.5	ENSP00000340474.4		Q8N9H8-1

Frequencies

GnomAD3 genomes

AF:

0.0370

AC:

5625

AN:

152178

Hom.:

161

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00885

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.0248

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0673

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0560

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0363

AC:

8331

AN:

229656

AF XY:

0.0380

show subpopulations

Gnomad AFR exome

AF:

0.00869

Gnomad AMR exome

AF:

0.0146

Gnomad ASJ exome

AF:

0.0195

Gnomad EAS exome

AF:

0.000340

Gnomad FIN exome

AF:

0.0653

Gnomad NFE exome

AF:

0.0516

Gnomad OTH exome

AF:

0.0367

GnomAD4 exome

AF:

0.0489

AC:

70751

AN:

1447858

Hom.:

1927

Cov.:

AF XY:

0.0488

AC XY:

35157

AN XY:

720032

show subpopulations

African (AFR)

AF:

0.00804

AC:

268

AN:

33344

American (AMR)

AF:

0.0148

AC:

646

AN:

43762

Ashkenazi Jewish (ASJ)

AF:

0.0201

AC:

519

AN:

25758

East Asian (EAS)

AF:

0.000126

AC:

AN:

39562

South Asian (SAS)

AF:

0.0311

AC:

2647

AN:

85164

European-Finnish (FIN)

AF:

0.0652

AC:

2967

AN:

45498

Middle Eastern (MID)

AF:

0.0351

AC:

196

AN:

5592

European-Non Finnish (NFE)

AF:

0.0549

AC:

60860

AN:

1109144

Other (OTH)

AF:

0.0440

AC:

2643

AN:

60034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

3835

7669

11504

15338

19173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2198

4396

6594

8792

10990

<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:

0.0369

AC:

5624

AN:

152296

Hom.:

161

Cov.:

AF XY:

0.0372

AC XY:

2771

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00883

AC:

367

AN:

41568

American (AMR)

AF:

0.0248

AC:

379

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.0236

AC:

114

AN:

4832

European-Finnish (FIN)

AF:

0.0673

AC:

715

AN:

10618

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0560

AC:

3811

AN:

68008

Other (OTH)

AF:

0.0222

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

284

567

851

1134

1418

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0472

Hom.:

233

Bravo

AF:

0.0311

TwinsUK

AF:

0.0520

AC:

193

ALSPAC

AF:

0.0493

AC:

190

ESP6500AA

AF:

0.0101

AC:

ESP6500EA

AF:

0.0500

AC:

422

ExAC

AF:

0.0358

AC:

4282

Asia WGS

AF:

0.00895

AC:

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

0.11

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.038

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.4

PhyloP100

2.0

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.10

Sift

Benign

0.091

Sift4G

Uncertain

0.018

Polyphen

0.90

Vest4

0.077

MPC

0.23

ClinPred

0.012

GERP RS

0.65

Varity_R

0.073

gMVP

0.21

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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