14-103698914-C-T

Position:

• chr14-103698914-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_005432.4(XRCC3):​c.925G>A​(p.Gly309Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,600,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: XRCC3 NM_005432.4 missense
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: -0.206

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011938393).
• BP6: Variant 14-103698914-C-T is Benign according to our data. Variant chr14-103698914-C-T is described in ClinVar as [Benign]. Clinvar id is 1050194.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC3	NM_005432.4	c.925G>A	p.Gly309Ser	missense_variant	10/10	ENST00000555055.6
KLC1	NM_001394837.1	c.1849-1741C>T		intron_variant		ENST00000334553.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC3	ENST00000555055.6	c.925G>A	p.Gly309Ser	missense_variant	10/10	1	NM_005432.4	P1
KLC1	ENST00000334553.11	c.1849-1741C>T		intron_variant		5	NM_001394837.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000284 AC: 63 AN: 222118 Hom.: 0 AF XY: 0.000364 AC XY: 44 AN XY: 120878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000180

Gnomad SAS exome AF: 0.00210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000133 AC: 193 AN: 1448132 Hom.: 0 Cov.: 31 AF XY: 0.000195 AC XY: 140 AN XY: 719168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000904

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74458

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000322 AC: 39

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The XRCC3 p.Gly309Ser variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs532124840) and in control databases in 65 of 253456 chromosomes at a frequency of 0.0002565 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 59 of 28102 chromosomes (freq: 0.002099), East Asian in 3 of 18218 chromosomes (freq: 0.000165), Other in 1 of 6638 chromosomes (freq: 0.000151) and European (non-Finnish) in 2 of 113534 chromosomes (freq: 0.000018), but was not observed in the African, Latino, Ashkenazi Jewish, or European (Finnish) populations. The p.Gly309 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.5
DANN	Benign	0.70
DEOGEN2	Benign	0.048	T;T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.31	N
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.80	N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.93	N;N;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.76	T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T
Polyphen		0.059	B;B;B;B;.
Vest4		0.17
MutPred		0.64		Gain of disorder (P = 0.0493);Gain of disorder (P = 0.0493);Gain of disorder (P = 0.0493);Gain of disorder (P = 0.0493);.;
MVP		0.48
MPC		0.19
ClinPred		0.015	T
GERP RS		-0.90
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.3
Varity_R		0.057
gMVP		0.58

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: rs532124840; hg19: chr14-104165251; COSMIC: COSV100572559; COSMIC: COSV100572559;