rs980673532

chr17-35119119-A-Cchr17-35119119-A-Gchr17-35119119-A-T

Variant summary

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

The NM_002878.4(RAD51D):c.136T>G(p.Ser46Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S46C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.01

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51D	NM_002878.4	c.136T>G	p.Ser46Ala	missense_variant	2/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1	n.232+2172T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11	c.136T>G	p.Ser46Ala	missense_variant	2/10	1	NM_002878.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 09, 2022	The p.S46A variant (also known as c.136T>G), located in coding exon 2 of the RAD51D gene, results from a T to G substitution at nucleotide position 136. The serine at codon 46 is replaced by alanine, an amino acid with similar 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2023	This missense variant replaces serine with alanine at codon 46 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	0.19
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;.;.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.61	D;D;D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.7	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
PROVEAN	Benign	-2.1	N;N;N;.;.
REVEL	Benign	0.14
Sift	Benign	0.056	T;T;D;.;.
Sift4G	Benign	0.23	T;T;D;T;.
Polyphen		0.97	D;D;D;.;.
Vest4		0.73
MutPred		0.50		Gain of helix (P = 0.005);Gain of helix (P = 0.005);Gain of helix (P = 0.005);Gain of helix (P = 0.005);.;
MVP		0.93
MPC		0.29
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.28
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs980673532; hg19: chr17-33446138;