rs3212057

chr14-103707128-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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, single submitter B:1
• Conservation: PhyloP100: 2.21

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 -14 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 id is 1336812.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC3	NM_005432.4	c.281G>A	p.Arg94His	missense_variant	6/10	ENST00000555055.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC3	ENST00000555055.6	c.281G>A	p.Arg94His	missense_variant	6/10	1	NM_005432.4	P1

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

GnomAD3 exomes AF: 0.00137 AC: 204 AN: 149336 Hom.: 2 AF XY: 0.00105 AC XY: 84 AN XY: 79774

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 SAS exome AF: 0.0000443

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

Gnomad4 AFR exome AF: 0.0217

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000213

Gnomad4 OTH exome AF: 0.00107

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

Gnomad4 AFR AF: 0.0215

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;.;.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.27	N
MetaRNN	Benign	0.0093	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.17	T;T;T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T;.;T
Polyphen		0.33	B;B;B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs3212057; hg19: chr14-104173465;