Variant rs1555429623 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5

The NM_002875.5(RAD51):c.749G>A(p.Arg250Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,732 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RAD51
NM_002875.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.97

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a helix (size 21) in uniprot entity RAD51_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002875.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RAD51. . Gene score misZ 2.622 (greater than the threshold 3.09). Trascript score misZ 3.642 (greater than threshold 3.09). GenCC has associacion of gene with Fanconi anemia, hereditary breast carcinoma, familial congenital mirror movements, mirror movements 2, Fanconi anemia complementation group R.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.835

PP5

Variant 15-40729609-G-A is Pathogenic according to our data. Variant chr15-40729609-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 471141.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-40729609-G-A is described in Lovd as [Likely_pathogenic]. Variant chr15-40729609-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51	NM_002875.5 linkuse as main transcript	c.749G>A	p.Arg250Gln	missense_variant	8/10	ENST00000267868.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51	ENST00000267868.8 linkuse as main transcript	c.749G>A	p.Arg250Gln	missense_variant	8/10	1	NM_002875.5	P1	Q06609-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727152

show subpopulations

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Mirror movements 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

.;T;.;.;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;.;D;.

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.5

M;M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.8

D;D;D;D;D;.

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0050

D;D;D;D;D;.

Sift4G

Uncertain

0.033

D;T;T;D;D;.

Polyphen

1.0

D;P;.;.;.;.

Vest4

0.86

MutPred

0.53

Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);.;.;.;Loss of MoRF binding (P = 0.018);

MVP

0.65

MPC

2.0

ClinPred

1.0

GERP RS

5.5

Varity_R

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.20

Position offset: 25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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