chr14-103699590-T-C

Position:

• chr14-103699590-T-C

Variant summary

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

The NM_005432.4(XRCC3):​c.562-14A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,612,304 control chromosomes in the GnomAD database, including 81,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.28 (6740 hom., cov: 31)
  • Exomes 𝑓: 0.31 (74479 hom.)
• Consequence: XRCC3 NM_005432.4 splice_polypyrimidine_tract, intron
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: -5.33

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLC1	NM_001394837.1	c.1849-1065T>C		intron_variant		ENST00000334553.11	NP_001381766.1
XRCC3	NM_005432.4	c.562-14A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000555055.6	NP_005423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLC1	ENST00000334553.11	c.1849-1065T>C		intron_variant		5	NM_001394837.1	ENSP00000334523
XRCC3	ENST00000555055.6	c.562-14A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005432.4	ENSP00000452598	P1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42601 AN: 151724 Hom.: 6727 Cov.: 31

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.261

GnomAD3 exomes AF: 0.308 AC: 76441 AN: 248434 Hom.: 12508 AF XY: 0.301 AC XY: 40614 AN XY: 134760

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.342

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.363

Gnomad SAS exome AF: 0.203

Gnomad FIN exome AF: 0.425

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.301

GnomAD4 exome AF: 0.315 AC: 459606 AN: 1460462 Hom.: 74479 Cov.: 36 AF XY: 0.310 AC XY: 225490 AN XY: 726574

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.213

Gnomad4 EAS exome AF: 0.340

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.421

Gnomad4 NFE exome AF: 0.326

Gnomad4 OTH exome AF: 0.293

GnomAD4 genome AF: 0.281 AC: 42630 AN: 151842 Hom.: 6740 Cov.: 31 AF XY: 0.282 AC XY: 20935 AN XY: 74212

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.290

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.358

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.434

Gnomad4 NFE AF: 0.333

Gnomad4 OTH AF: 0.263

Alfa AF: 0.299 Hom.: 1366

Bravo AF: 0.265

Asia WGS AF: 0.262 AC: 910 AN: 3478

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Breast cancer, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.035
DANN	Benign	0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1799796; hg19: chr14-104165927; COSMIC: COSV57975256; COSMIC: COSV57975256;