rs1272809785

Positions:

• chr17-35107111-A-C
• chr17-35107111-A-G
• chr17-35107111-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002878.4(RAD51D):​c.357T>G​(p.Cys119Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.786

Genes affected

RAD51D (HGNC:9823): (RAD51 paralog D) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]

ENSG00000267618 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.357T>G	p.Cys119Trp	missense_variant	5/10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.357T>G	p.Cys119Trp	missense_variant	5/10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5	c.4-630T>G		intron_variant		2		ENSP00000466834.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2023

The p.C119W variant (also known as c.357T>G), located in coding exon 5 of the RAD51D gene, results from a T to G substitution at nucleotide position 357. The cysteine at codon 119 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;.;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	.;T;T;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	2.9	M;M;.;.
PROVEAN	Benign	-2.3	N;.;.;.
REVEL	Benign	0.24
Sift	Uncertain	0.022	D;.;.;.
Sift4G	Benign	0.18	T;T;T;.
Polyphen		1.0	D;D;.;.
Vest4		0.56
MutPred		0.66		Gain of MoRF binding (P = 0.2565);Gain of MoRF binding (P = 0.2565);.;.;
MVP		0.98
MPC		0.50
ClinPred		0.97	D
GERP RS		2.3
Varity_R		0.33
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-33434130;