rs1057519413

chr15-40729955-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_002875.5(RAD51):c.877G>A(p.Ala293Thr) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A293A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAD51 NM_002875.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 9.61

Genes affected

RAD51 (HGNC:9817): (RAD51 recombinase) 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, and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with the ssDNA-binding protein RPA and RAD52, and it is thought to play roles in homologous pairing and strand transfer of DNA. This protein is also found to interact with BRCA1 and BRCA2, which may be important for the cellular response to DNA damage. BRCA2 is shown to regulate both the intracellular localization and DNA-binding ability of this protein. Loss of these controls following BRCA2 inactivation may be a key event leading to genomic instability and tumorigenesis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RAD51
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 15-40729955-G-A is Pathogenic according to our data. Variant chr15-40729955-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40729955-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51	NM_002875.5	c.877G>A	p.Ala293Thr	missense_variant	9/10	ENST00000267868.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51	ENST00000267868.8	c.877G>A	p.Ala293Thr	missense_variant	9/10	1	NM_002875.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RAD51-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2022

The RAD51 c.880G>A variant is predicted to result in the amino acid substitution p.Ala294Thr. This variant has been reported as arising de novo in an individual with microcephaly and intellectual disability, and described as atypical Fanconi anemia (reported as p.Ala293Thr in alternate transcript NM_002875 in Ameziane et al. 2015. PubMed ID: 26681308). Functional studies from this same report using protein expression in cultured cells indicate that the p.Ala294Thr substitution has a dominant negative effect on the wild-type protein (Ameziane et al. 2015. PubMed ID: 26681308). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret c.880G>A (p.Ala294Thr) as likely pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2016

- -

Fanconi anemia complementation group R Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 10, 2020

- -

RAD51-related disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Aug 25, 2020

This variant has been previously reported as a de novo alteration in a patient with an atypical Fanconi Anemia who presented with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle (NM_002875.3: c.877G>A, p.A293T; PMID: 26681308). In vitro characterization of this alteration via functional assays and biochemical studies demonstrated that the variant acts in a dominant-negative manner leading to impaired DNA binding and strand exchange activity as well as impaired ATP hydrolysis. Furthermore, patient's cells were sensitive to DNA crosslinking agents (PMID: 26681308). The c.880G>A p.Ala294Thr variant is absent from the gnomAD population database and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.880G>A (p.Ala294Thr) variant is classified as Pathogenic. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

curation

Leiden Open Variation Database

Mar 15, 2014

Curator: Arleen D. Auerbach. Submitter to LOVD: Najim Ameziane. Comment: Variant observed de novo. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.068	D
MutationAssessor	Pathogenic	3.3	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D
Polyphen		0.97	D;.;.;.
Vest4		0.81
MutPred		0.82		Gain of glycosylation at A293 (P = 0.1028);.;.;.;
MVP		0.78
MPC		2.0
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1057519413; hg19: chr15-41022153;