14-103698934-C-T

Variant names:

• chr14-103698934-C-T
• rs28903081
• NM_005432.4:c.905G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_005432.4(XRCC3):​c.905G>A​(p.Arg302His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,600,194 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R302C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: XRCC3 NM_005432.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.581
• Publications: 16 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004445195).
• BP6: Variant 14-103698934-C-T is Benign according to our data. Variant chr14-103698934-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3033087.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC3	NM_005432.4	MANE Select	c.905G>A	p.Arg302His	missense	Exon 10 of 10	NP_005423.1	O43542
	KLC1	NM_001394837.1	MANE Select	c.1849-1721C>T		intron	N/A	NP_001381766.1	Q07866-9
	XRCC3	NM_001100118.2		c.905G>A	p.Arg302His	missense	Exon 9 of 9	NP_001093588.1	Q53XC8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC3	ENST00000555055.6	TSL:1 MANE Select	c.905G>A	p.Arg302His	missense	Exon 10 of 10	ENSP00000452598.1	O43542
	XRCC3	ENST00000352127.11	TSL:1	c.905G>A	p.Arg302His	missense	Exon 9 of 9	ENSP00000343392.7	O43542
	KLC1	ENST00000334553.11	TSL:5 MANE Select	c.1849-1721C>T		intron	N/A	ENSP00000334523.6	Q07866-9

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152208 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00439

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000430 AC: 96 AN: 223288 AF XY: 0.000296

Gnomad AFR exome AF: 0.00490

Gnomad AMR exome AF: 0.000186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.000383 AC: 554 AN: 1447868 Hom.: 1 Cov.: 31 AF XY: 0.000359 AC XY: 258 AN XY: 719048

African (AFR) AF: 0.00458 AC: 152 AN: 33188

American (AMR) AF: 0.000162 AC: 7 AN: 43108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.0000768 AC: 3 AN: 39050

South Asian (SAS) AF: 0.0000356 AC: 3 AN: 84186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51296

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5744

European-Non Finnish (NFE) AF: 0.000305 AC: 337 AN: 1105640

Other (OTH) AF: 0.000819 AC: 49 AN: 59810

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152326 Hom.: 1 Cov.: 33 AF XY: 0.00134 AC XY: 100 AN XY: 74480

African (AFR) AF: 0.00440 AC: 183 AN: 41576

American (AMR) AF: 0.000457 AC: 7 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000740 Hom.: 0

Bravo AF: 0.00162

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00387 AC: 17

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000446 AC: 54

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	XRCC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.9
DANN	Benign	0.97
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.58
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.046
Sift	Benign	0.40	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.074
MVP		0.34
MPC		0.23
ClinPred		0.0049	T
GERP RS		-1.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.048
gMVP		0.51
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs28903081; hg19: chr14-104165271;