rs372082751

chr17-35119610-C-Achr17-35119610-C-Gchr17-35119610-C-T

Variant summary

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

The NM_002878.4(RAD51D):c.4G>T(p.Gly2Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,912 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G2A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.99

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.4G>T	p.Gly2Cys	missense_variant	1/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1	n.232+1681G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11	c.4G>T	p.Gly2Cys	missense_variant	1/10	1	NM_002878.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246552 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458912 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725926

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 09, 2016

This variant is denoted RAD51D c.4G>T at the cDNA level, p.Gly2Cys (G2C) at the protein level, and results in the change of a Glycine to a Cysteine (GGC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Gly2Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51D Gly2Cys occurs at a position where amino acids with properties similar to Glycine are tolerated across species and is located in the region that preferentially binds ssDNA (Kim 2011, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. This variant occurs in a conserved nucleotide in the Kozak consensus sequence and therefore may impact protein translation; however, in the absence of functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether RAD51D Gly2Cys is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 02, 2021

This sequence change replaces glycine with cysteine at codon 2 of the RAD51D protein (p.Gly2Cys). The glycine residue is weakly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is present in population databases (rs372082751, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 421161). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.0089	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.3	M;M;M;M
MutationTaster	Benign	0.90	D;D;D;D;D;D;N
PROVEAN	Benign	-2.0	N;N;D;.
REVEL	Benign	0.15
Sift	Benign	0.093	T;T;T;.
Sift4G	Benign	0.10	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.36
MutPred		0.46		Loss of disorder (P = 0);Loss of disorder (P = 0);Loss of disorder (P = 0);Loss of disorder (P = 0);
MVP		0.86
MPC		0.43
ClinPred		0.95	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.38
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs372082751; hg19: chr17-33446629;