14-103699486-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005432.4(XRCC3):​c.652C>G​(p.Pro218Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. P218S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

XRCC3
NM_005432.4 missense

Scores

5
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.75
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.33187193).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
XRCC3NM_005432.4 linkc.652C>G p.Pro218Ala missense_variant Exon 8 of 10 ENST00000555055.6 NP_005423.1 O43542Q53XC8
KLC1NM_001394837.1 linkc.1849-1169G>C intron_variant Intron 15 of 16 ENST00000334553.11 NP_001381766.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
XRCC3ENST00000555055.6 linkc.652C>G p.Pro218Ala missense_variant Exon 8 of 10 1 NM_005432.4 ENSP00000452598.1 O43542
KLC1ENST00000334553.11 linkc.1849-1169G>C intron_variant Intron 15 of 16 5 NM_001394837.1 ENSP00000334523.6 Q07866-9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460722
Hom.:
0
Cov.:
34
AF XY:
0.00000275
AC XY:
2
AN XY:
726700
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.015
T
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.049
T;T;T;T;T
Eigen
Benign
0.12
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.88
.;.;.;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.33
T;T;T;T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Uncertain
2.3
M;M;M;M;.
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.92
N;N;N;N;N
REVEL
Benign
0.13
Sift
Benign
0.16
T;T;T;T;T
Sift4G
Benign
0.12
T;T;T;T;T
Polyphen
0.42
B;B;B;B;.
Vest4
0.44
MutPred
0.51
Gain of catalytic residue at S214 (P = 2e-04);Gain of catalytic residue at S214 (P = 2e-04);Gain of catalytic residue at S214 (P = 2e-04);Gain of catalytic residue at S214 (P = 2e-04);.;
MVP
0.68
MPC
0.31
ClinPred
0.64
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.22
gMVP
0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-104165823; API