rs35097575

Positions:

• chr9-137349428-G-A
• chr9-137349428-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.96

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 402840.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
EXD3	NM_017820.5	c.1598C>T	p.Thr533Met	missense_variant	15/22	ENST00000340951.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXD3	ENST00000340951.9	c.1598C>T	p.Thr533Met	missense_variant	15/22	1	NM_017820.5	P1

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5625 AN: 152178 Hom.: 161 Cov.: 32

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

GnomAD3 exomes AF: 0.0363 AC: 8331 AN: 229656 Hom.: 213 AF XY: 0.0380 AC XY: 4793 AN XY: 126180

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 SAS exome AF: 0.0296

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.: 35 AF XY: 0.0488 AC XY: 35157 AN XY: 720032

Gnomad4 AFR exome AF: 0.00804

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.0201

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0311

Gnomad4 FIN exome AF: 0.0652

Gnomad4 NFE exome AF: 0.0549

Gnomad4 OTH exome AF: 0.0440

GnomAD4 genome AF: 0.0369 AC: 5624 AN: 152296 Hom.: 161 Cov.: 32 AF XY: 0.0372 AC XY: 2771 AN XY: 74474

Gnomad4 AFR AF: 0.00883

Gnomad4 AMR AF: 0.0248

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0236

Gnomad4 FIN AF: 0.0673

Gnomad4 NFE AF: 0.0560

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0470 Hom.: 189

Bravo AF: 0.0311

TwinsUK AF: 0.0520 AC: 193

ALSPAC AF: 0.0493 AC: 190

ESP6500AA AF: 0.0101 AC: 43

ESP6500EA AF: 0.0500 AC: 422

ExAC AF: 0.0358 AC: 4282

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.10
Sift	Benign	0.091	T
Sift4G	Uncertain	0.018	D
Polyphen		0.90	P
Vest4		0.077
MPC		0.23
ClinPred		0.012	T
GERP RS		0.65
Varity_R		0.073
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs35097575; hg19: chr9-140243880;