chr15-40729955-G-A

Variant names:

• chr15-40729955-G-A
• rs1057519413
• NM_002875.5:c.877G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 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
• Publications: 17 publications found

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]

RAD51 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group R

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mirror movements 2

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• familial congenital mirror movements

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_002875.5
• PM2: Very rare variant in population databases, with high coverage
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 372139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51	NM_002875.5	c.877G>A	p.Ala293Thr	missense_variant	Exon 9 of 10	ENST00000267868.8	NP_002866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51	ENST00000267868.8	c.877G>A	p.Ala293Thr	missense_variant	Exon 9 of 10	1	NM_002875.5	ENSP00000267868.3
RAD51	ENST00000532743.6	c.877G>A	p.Ala293Thr	missense_variant	Exon 9 of 10	2		ENSP00000433924.2
RAD51	ENST00000557850.5	c.586G>A	p.Ala196Thr	missense_variant	Exon 7 of 8	2		ENSP00000454176.1

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 disorder Pathogenic:2

Sep 20, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 25, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases Pathogenic:1

Nov 15, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group R Pathogenic:1

Jun 10, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Mar 15, 2014

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

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;.;.;.
PhyloP100		9.6
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519413; hg19: chr15-41022153;