rs1219993160

Variant names:

• chr14-103699515-C-A
• rs1219993160
• NM_005432.4:c.623G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-103699515-C-A
• chr14-103699515-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005432.4(XRCC3):​c.623G>T​(p.Arg208Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: XRCC3 NM_005432.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.76
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

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.623G>T	p.Arg208Leu	missense	Exon 8 of 10	NP_005423.1	O43542
	KLC1	NM_001394837.1	MANE Select	c.1849-1140C>A		intron	N/A	NP_001381766.1	Q07866-9
	XRCC3	NM_001100118.2		c.623G>T	p.Arg208Leu	missense	Exon 7 of 9	NP_001093588.1	Q53XC8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC3	ENST00000555055.6	TSL:1 MANE Select	c.623G>T	p.Arg208Leu	missense	Exon 8 of 10	ENSP00000452598.1	O43542
	XRCC3	ENST00000352127.11	TSL:1	c.623G>T	p.Arg208Leu	missense	Exon 7 of 9	ENSP00000343392.7	O43542
	KLC1	ENST00000334553.11	TSL:5 MANE Select	c.1849-1140C>A		intron	N/A	ENSP00000334523.6	Q07866-9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460960 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726798

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.011	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.90
MutPred		0.66		Gain of catalytic residue at S203 (P = 0.0018)
MVP		0.90
MPC		0.81
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.80
Mutation Taster		=32/68	disease causing

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: rs1219993160; hg19: chr14-104165852;