chr14-103699416-G-A

Variant names:

• chr14-103699416-G-A
• rs861539
• NM_005432.4:c.722C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 14/21 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, single submitter B:2 O:1
• Conservation: PhyloP100: 0.797
• Publications: 705 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005432.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC3	NM_005432.4	MANE Select	c.722C>T	p.Thr241Met	missense	Exon 8 of 10	NP_005423.1
	KLC1	NM_001394837.1	MANE Select	c.1849-1239G>A		intron	N/A	NP_001381766.1
	XRCC3	NM_001100118.2		c.722C>T	p.Thr241Met	missense	Exon 7 of 9	NP_001093588.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC3	ENST00000555055.6	TSL:1 MANE Select	c.722C>T	p.Thr241Met	missense	Exon 8 of 10	ENSP00000452598.1
	XRCC3	ENST00000352127.11	TSL:1	c.722C>T	p.Thr241Met	missense	Exon 7 of 9	ENSP00000343392.7
	KLC1	ENST00000334553.11	TSL:5 MANE Select	c.1849-1239G>A		intron	N/A	ENSP00000334523.6

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

GnomAD2 exomes AF: 0.290 AC: 71621 AN: 246952 AF XY: 0.298

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 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

African (AFR) AF: 0.214 AC: 7151 AN: 33466

American (AMR) AF: 0.184 AC: 8191 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 10507 AN: 26110

East Asian (EAS) AF: 0.0738 AC: 2928 AN: 39694

South Asian (SAS) AF: 0.252 AC: 21699 AN: 86230

European-Finnish (FIN) AF: 0.303 AC: 15836 AN: 52302

Middle Eastern (MID) AF: 0.387 AC: 2159 AN: 5578

European-Non Finnish (NFE) AF: 0.374 AC: 416286 AN: 1111596

Other (OTH) AF: 0.328 AC: 19757 AN: 60304

GnomAD4 genome AF: 0.298 AC: 45218 AN: 151936 Hom.: 7378 Cov.: 32 AF XY: 0.291 AC XY: 21629 AN XY: 74296

African (AFR) AF: 0.209 AC: 8659 AN: 41444

American (AMR) AF: 0.259 AC: 3960 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1434 AN: 3472

East Asian (EAS) AF: 0.0654 AC: 337 AN: 5152

South Asian (SAS) AF: 0.234 AC: 1123 AN: 4798

European-Finnish (FIN) AF: 0.288 AC: 3049 AN: 10590

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25486 AN: 67878

Other (OTH) AF: 0.316 AC: 665 AN: 2106

Alfa AF: 0.351 Hom.: 44376

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	XRCC3-related disorder (1)
-	-	-	Melanoma, cutaneous malignant, susceptibility to, 6 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.80
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.031
Sift	Benign	0.14	T
Sift4G	Benign	0.10	T
Polyphen		0.54	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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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