chr17-35107376-C-G

Position:

• chr17-35107376-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_002878.4(RAD51D):​c.335G>C​(p.Gly112Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000712 in 1,403,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G112D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.55

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 17-35107376-C-G is Pathogenic according to our data. Variant chr17-35107376-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234081.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51D	NM_002878.4	c.335G>C	p.Gly112Ala	missense_variant	4/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1	n.233-895G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11	c.335G>C	p.Gly112Ala	missense_variant	4/10	1	NM_002878.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403932 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 701156

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: 9.44e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2015

The p.G112A variant (also known as c.335G>C), located in coding exon 4 of the RAD51D gene, results from a G to C substitution at nucleotide position 335. The glycine at codon 112 is replaced by alanine, an amino acid with similar properties. This alteration was shown to have reduced repair of DNA interstrand crosslinks and also reduced interactions with DNA repair binding partners RAD51C and XRCC2 (Gruver AM et al. Mutagenesis 2005 Nov; 20(6):433-40). In addition, internal structural analysis predicts that this alteration causes destabilization of a critical functional motif leading to loss or impairment of ATPase function (Walker J et al. EMBO J. 1982; 1(8):945-51). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 13, 2021

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 RAD51D protein function. 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. This variant has not been reported in the literature in individuals with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 234081). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 112 of the RAD51D protein (p.Gly112Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. Experimental studies have shown that this variant affects RAD51D protein function (PMID: 16236763). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T;.;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Pathogenic	-5.1	D;.;.;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0070	D;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.93
MutPred		0.87		Loss of glycosylation at S111 (P = 0.0534);Loss of glycosylation at S111 (P = 0.0534);.;.;
MVP		0.99
MPC		0.47
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.85
gMVP		0.83

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: rs587782848; hg19: chr17-33434395;