rs3212057

Variant names:

• chr14-103707128-C-T
• rs3212057
• NM_005432.4:c.281G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005432.4(XRCC3):​c.281G>A​(p.Arg94His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,549,774 control chromosomes in the GnomAD database, including 16 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (9 hom., cov: 34)
  • Exomes 𝑓: 0.00059 (7 hom.)
• Consequence: XRCC3 NM_005432.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.21
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009322435).
• BP6: Variant 14-103707128-C-T is Benign according to our data. Variant chr14-103707128-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1336812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00608 (927/152366) while in subpopulation AFR AF = 0.0215 (893/41576). AF 95% confidence interval is 0.0203. There are 9 homozygotes in GnomAd4. There are 426 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 gene

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.281G>A	p.Arg94His	missense	Exon 6 of 10	NP_005423.1	O43542
	XRCC3	NM_001100118.2		c.281G>A	p.Arg94His	missense	Exon 5 of 9	NP_001093588.1	Q53XC8
	XRCC3	NM_001100119.2		c.281G>A	p.Arg94His	missense	Exon 6 of 10	NP_001093589.1	O43542

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC3	ENST00000555055.6	TSL:1 MANE Select	c.281G>A	p.Arg94His	missense	Exon 6 of 10	ENSP00000452598.1	O43542
	XRCC3	ENST00000352127.11	TSL:1	c.281G>A	p.Arg94His	missense	Exon 5 of 9	ENSP00000343392.7	O43542
	KLC1	ENST00000348520.10	TSL:1	c.*5929C>T		3_prime_UTR	Exon 15 of 15	ENSP00000341154.6	Q07866-1

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 927 AN: 152248 Hom.: 9 Cov.: 34

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00137 AC: 204 AN: 149336 AF XY: 0.00105

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.000976

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000717

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000590 AC: 825 AN: 1397408 Hom.: 7 Cov.: 31 AF XY: 0.000486 AC XY: 335 AN XY: 689310

African (AFR) AF: 0.0217 AC: 684 AN: 31582

American (AMR) AF: 0.00123 AC: 44 AN: 35730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00 AC: 0 AN: 35754

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48000

Middle Eastern (MID) AF: 0.00171 AC: 9 AN: 5256

European-Non Finnish (NFE) AF: 0.0000213 AC: 23 AN: 1078844

Other (OTH) AF: 0.00107 AC: 62 AN: 57916

GnomAD4 genome AF: 0.00608 AC: 927 AN: 152366 Hom.: 9 Cov.: 34 AF XY: 0.00572 AC XY: 426 AN XY: 74508

African (AFR) AF: 0.0215 AC: 893 AN: 41576

American (AMR) AF: 0.00170 AC: 26 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00179 Hom.: 1

Bravo AF: 0.00662

ESP6500AA AF: 0.0185 AC: 77

ESP6500EA AF: 0.000124 AC: 1

ExAC AF: 0.00109 AC: 100

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.2
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.078
Sift	Benign	0.17	T
Sift4G	Benign	0.16	T
Polyphen		0.33	B
Vest4		0.12
MVP		0.82
MPC		0.26
ClinPred		0.010	T
GERP RS		3.9
Varity_R		0.059
gMVP		0.60
Mutation Taster		=100/0	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: rs3212057; hg19: chr14-104173465;