Variant 9-137307042-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_017820.5(EXD3):c.2539C>T(p.Arg847Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,612,248 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R847H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 8 hom. )

Consequence

EXD3
NM_017820.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11183414).

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXD3	NM_017820.5 linkuse as main transcript	c.2539C>T	p.Arg847Cys	missense_variant	22/22	ENST00000340951.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXD3	ENST00000340951.9 linkuse as main transcript	c.2539C>T	p.Arg847Cys	missense_variant	22/22	1	NM_017820.5	P1	Q8N9H8-1
EXD3	ENST00000491734.6 linkuse as main transcript	c.*1607C>T		3_prime_UTR_variant, NMD_transcript_variant	15/15	1
EXD3	ENST00000487745.5 linkuse as main transcript	n.1867C>T		non_coding_transcript_exon_variant	12/12	2

Frequencies

GnomAD3 genomes

AF:

0.00134

AC:

204

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00112

AC:

274

AN:

244636

Hom.:

AF XY:

0.00111

AC XY:

148

AN XY:

133622

show subpopulations

Gnomad AFR exome

AF:

0.000132

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.000504

Gnomad EAS exome

AF:

0.0000559

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00275

Gnomad NFE exome

AF:

0.00179

Gnomad OTH exome

AF:

0.00101

GnomAD4 exome

AF:

0.00194

AC:

2827

AN:

1460016

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

1375

AN XY:

726290

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.000498

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00244

Gnomad4 NFE exome

AF:

0.00233

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.00134

AC:

204

AN:

152232

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00283

Gnomad4 NFE

AF:

0.00226

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00163

Hom.:

Bravo

AF:

0.00115

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000244

AC:

ESP6500EA

AF:

0.00215

AC:

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00158

EpiControl

AF:

0.00154

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.2539C>T (p.R847C) alteration is located in exon 22 (coding exon 21) of the EXD3 gene. This alteration results from a C to T substitution at nucleotide position 2539, causing the arginine (R) at amino acid position 847 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.42

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0050

Polyphen

0.63

Vest4

0.59

MVP

0.43

MPC

0.40

ClinPred

0.084

GERP RS

2.0

Varity_R

0.13

gMVP

0.65

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