chr17-35101015-C-A

Position:

• chr17-35101015-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002878.4(RAD51D):​c.925G>T​(p.Val309Leu) 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 benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V309I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.121

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]

RAD51L3-RFFL (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1052264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51D	NM_002878.4	c.925G>T	p.Val309Leu	missense_variant	10/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1	n.655+186G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11	c.925G>T	p.Val309Leu	missense_variant	10/10	1	NM_002878.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Color Diagnostics, LLC DBA Color Health

Dec 05, 2023

This missense variant replaces valine with leucine at codon 309 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RAD51D-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.7
DANN	Benign	0.89
DEOGEN2	Benign	0.083	T;T;.;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.72	.;T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Benign	-0.29	N;.;.;.;.
REVEL	Benign	0.061
Sift	Benign	0.36	T;.;.;.;.
Sift4G	Benign	0.74	T;T;T;T;T
Polyphen		0.0010	B;B;B;.;.
Vest4		0.029
MutPred		0.71		Gain of catalytic residue at V309 (P = 0.0205);Gain of catalytic residue at V309 (P = 0.0205);.;.;.;
MVP		0.56
MPC		0.082
ClinPred		0.11	T
GERP RS		0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.32

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

Other links and lift over

dbSNP: rs1555566979; hg19: chr17-33428034;