rs861539

Positions:

chr14-103699416-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_005432.4(XRCC3):c.722C>T(p.Thr241Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,611,814 control chromosomes in the GnomAD database, including 98,522 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.30 ( 7378 hom., cov: 32)

Exomes 𝑓: 0.35 ( 91144 hom. )

Consequence

XRCC3
NM_005432.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 0.797

Variant links:

Genes affected

XRCC3 (HGNC:12830): (X-ray repair cross complementing 3) This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene functionally complements Chinese hamster irs1SF, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents and is chromosomally unstable. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

XRCC3 links:

KLC1 (HGNC:6387): (kinesin light chain 1) Conventional kinesin is a tetrameric molecule composed of two heavy chains and two light chains, and transports various cargos along microtubules toward their plus ends. The heavy chains provide the motor activity, while the light chains bind to various cargos. This gene encodes a member of the kinesin light chain family. It associates with kinesin heavy chain through an N-terminal domain, and six tetratricopeptide repeat (TPR) motifs are thought to be involved in binding of cargos such as vesicles, mitochondria, and the Golgi complex. Thus, kinesin light chains function as adapter molecules and not motors per se. Although previously named "kinesin 2", this gene is not a member of the kinesin-2 / kinesin heavy chain subfamily of kinesin motor proteins. Extensive alternative splicing produces isoforms with different C-termini that are proposed to bind to different cargos; however, the full-length nature and/or biological validity of most of these variants have not been determined. [provided by RefSeq, Jul 2008]

KLC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016989827).

BP6

Variant 14-103699416-G-A is Benign according to our data. Variant chr14-103699416-G-A is described in ClinVar as [Benign]. Clinvar id is 8944.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC3	NM_005432.4 linkuse as main transcript	c.722C>T	p.Thr241Met	missense_variant	8/10	ENST00000555055.6	NP_005423.1
KLC1	NM_001394837.1 linkuse as main transcript	c.1849-1239G>A		intron_variant		ENST00000334553.11	NP_001381766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC3	ENST00000555055.6 linkuse as main transcript	c.722C>T	p.Thr241Met	missense_variant	8/10	1	NM_005432.4	ENSP00000452598	P1
KLC1	ENST00000334553.11 linkuse as main transcript	c.1849-1239G>A		intron_variant		5	NM_001394837.1	ENSP00000334523		Q07866-9

Frequencies

GnomAD3 genomes

AF:

0.298

AC:

45211

AN:

151816

Hom.:

7375

Cov.:

show subpopulations

Gnomad AFR

AF:

0.209

Gnomad AMI

AF:

0.431

Gnomad AMR

AF:

0.259

Gnomad ASJ

AF:

0.413

Gnomad EAS

AF:

0.0653

Gnomad SAS

AF:

0.233

Gnomad FIN

AF:

0.288

Gnomad MID

AF:

0.376

Gnomad NFE

AF:

0.376

Gnomad OTH

AF:

0.320

GnomAD3 exomes

AF:

0.290

AC:

71621

AN:

246952

Hom.:

11812

AF XY:

0.298

AC XY:

40018

AN XY:

134296

show subpopulations

Gnomad AFR exome

AF:

0.207

Gnomad AMR exome

AF:

0.173

Gnomad ASJ exome

AF:

0.400

Gnomad EAS exome

AF:

0.0546

Gnomad SAS exome

AF:

0.243

Gnomad FIN exome

AF:

0.297

Gnomad NFE exome

AF:

0.377

Gnomad OTH exome

AF:

0.319

GnomAD4 exome

AF:

0.346

AC:

504514

AN:

1459878

Hom.:

91144

Cov.:

AF XY:

0.345

AC XY:

250452

AN XY:

726268

show subpopulations

Gnomad4 AFR exome

AF:

0.214

Gnomad4 AMR exome

AF:

0.184

Gnomad4 ASJ exome

AF:

0.402

Gnomad4 EAS exome

AF:

0.0738

Gnomad4 SAS exome

AF:

0.252

Gnomad4 FIN exome

AF:

0.303

Gnomad4 NFE exome

AF:

0.374

Gnomad4 OTH exome

AF:

0.328

GnomAD4 genome

AF:

0.298

AC:

45218

AN:

151936

Hom.:

7378

Cov.:

AF XY:

0.291

AC XY:

21629

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.209

Gnomad4 AMR

AF:

0.259

Gnomad4 ASJ

AF:

0.413

Gnomad4 EAS

AF:

0.0654

Gnomad4 SAS

AF:

0.234

Gnomad4 FIN

AF:

0.288

Gnomad4 NFE

AF:

0.375

Gnomad4 OTH

AF:

0.316

Alfa

AF:

0.362

Hom.:

21926

Bravo

AF:

0.292

TwinsUK

AF:

0.383

AC:

1419

ALSPAC

AF:

0.389

AC:

1498

ESP6500AA

AF:

0.216

AC:

950

ESP6500EA

AF:

0.378

AC:

3252

ExAC

AF:

0.292

AC:

35416

Asia WGS

AF:

0.125

AC:

438

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

XRCC3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 08, 2023

- -

Melanoma, cutaneous malignant, susceptibility to, 6

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Oct 15, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.6

DANN

Uncertain

1.0

DEOGEN2

Benign

0.043

T;T;T;T;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.54

.;.;.;T;T

MetaRNN

Benign

0.017

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.2

L;L;L;L;.

MutationTaster

Benign

1.0

P;P;P;P;P;P;P;P;P;P;P;P

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.1

N;N;N;N;N

REVEL

Benign

0.031

Sift

Benign

0.14

T;T;T;T;T

Sift4G

Benign

0.10

T;T;T;T;T

Polyphen

0.54

P;P;P;P;.

Vest4

0.051

MPC

0.19

ClinPred

0.0052

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.34

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

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