rs861539

chr14-103699416-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 12/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.797

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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	UniProt
XRCC3	NM_005432.4	c.722C>T	p.Thr241Met	missense_variant	8/10	ENST00000555055.6
KLC1	NM_001394837.1	c.1849-1239G>A		intron_variant		ENST00000334553.11

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45211 AN: 151816 Hom.: 7375 Cov.: 32

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

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.: 56 AF XY: 0.345 AC XY: 250452 AN XY: 726268

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.: 32 AF XY: 0.291 AC XY: 21629 AN XY: 74296

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:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

XRCC3-related condition Benign:1

Benign, criteria provided, single submitter

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

Invitae

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	T
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	N
MetaRNN	Benign	0.017	T;T;T;T;T
MetaSVM	Benign	-0.91	T
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	T
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	T
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

Other links and lift over

dbSNP: rs861539; hg19: chr14-104165753; COSMIC: COSV57974380; COSMIC: COSV57974380;