14-103712930-T-C

Variant names:

• chr14-103712930-T-C
• rs1799794
• NM_005432.4:c.-316A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005432.4(XRCC3):​c.-316A>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 152,408 control chromosomes in the GnomAD database, including 4,064 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (4058 hom., cov: 34)
  • Exomes 𝑓: 0.27 (6 hom.)
• Consequence: XRCC3 NM_005432.4 splice_region
• Scores: Splicing: ADA: 0.00007478
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.429

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC3	NM_005432.4	c.-316A>G		splice_region_variant	Exon 2 of 10	ENST00000555055.6	NP_005423.1
XRCC3	NM_005432.4	c.-316A>G		5_prime_UTR_variant	Exon 2 of 10	ENST00000555055.6	NP_005423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC3	ENST00000555055.6	c.-316A>G		splice_region_variant	Exon 2 of 10	1	NM_005432.4	ENSP00000452598.1
XRCC3	ENST00000555055.6	c.-316A>G		5_prime_UTR_variant	Exon 2 of 10	1	NM_005432.4	ENSP00000452598.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34020 AN: 152084 Hom.: 4052 Cov.: 34

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.275 AC: 56 AN: 204 Hom.: 6 Cov.: 0 AF XY: 0.279 AC XY: 43 AN XY: 154

Gnomad4 AFR exome AF: 0.500

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.400

Gnomad4 FIN exome AF: 0.417

Gnomad4 NFE exome AF: 0.253

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.224 AC: 34029 AN: 152204 Hom.: 4058 Cov.: 34 AF XY: 0.229 AC XY: 17042 AN XY: 74428

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.194

Gnomad4 OTH AF: 0.238

Alfa AF: 0.201 Hom.: 1332

Bravo AF: 0.219

Asia WGS AF: 0.416 AC: 1445 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000075
SpliceAI score (max)		0.020		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: rs1799794; hg19: chr14-104179267;