rs864622580

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_058216.3(RAD51C):ā€‹c.443T>Cā€‹(p.Phe148Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

4
10
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08
Variant links:
Genes affected
RAD51C (HGNC:9820): (RAD51 paralog C) This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAD51CNM_058216.3 linkuse as main transcriptc.443T>C p.Phe148Ser missense_variant 3/9 ENST00000337432.9 NP_478123.1 O43502-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAD51CENST00000337432.9 linkuse as main transcriptc.443T>C p.Phe148Ser missense_variant 3/91 NM_058216.3 ENSP00000336701.4 O43502-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461878
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727238
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 01, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAD51C protein function. ClinVar contains an entry for this variant (Variation ID: 220560). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 148 of the RAD51C protein (p.Phe148Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.046
T;T;T;T;T
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.93
D;D;D;D;D
M_CAP
Benign
0.019
T
MetaRNN
Uncertain
0.58
D;D;D;D;D
MetaSVM
Benign
-0.89
T
MutationAssessor
Uncertain
2.6
.;.;M;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-6.1
.;.;D;D;.
REVEL
Uncertain
0.36
Sift
Uncertain
0.0040
.;.;D;D;.
Sift4G
Benign
0.13
T;D;D;D;T
Polyphen
1.0
.;.;D;.;.
Vest4
0.80, 0.79
MutPred
0.43
.;Gain of glycosylation at F148 (P = 0.041);Gain of glycosylation at F148 (P = 0.041);.;.;
MVP
0.75
MPC
1.1
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.91
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs864622580; hg19: chr17-56774092; API