NM_002878.4:c.680T>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002878.4(RAD51D):c.680T>A(p.Met227Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M227I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.71

Publications

0 publications found

Variant links:

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]

RAD51D Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 4
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

RAD51D links:

ENSG00000267618 (HGNC:):

ENSG00000267618 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51D	NM_002878.4 link	c.680T>A	p.Met227Lys	missense_variant	Exon 8 of 10	ENST00000345365.11	NP_002869.3	O75771-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 link	c.680T>A	p.Met227Lys	missense_variant	Exon 8 of 10	1	NM_002878.4	ENSP00000338790.6		O75771-1
ENSG00000267618	ENST00000593039.5 link	c.203T>A	p.Met68Lys	missense_variant	Exon 4 of 7	2		ENSP00000466834.1		K7EN88

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000406

AC:

AN:

246306

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459996

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726102

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.0000225

AC:

AN:

44396

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

85764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111280

Other (OTH)

AF:

0.00

AC:

AN:

60342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.34

.;.;.;T;T;.;.;.;.;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;T;T;.;T;D;T;D;T;T

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.89

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Pathogenic

3.0

.;.;.;M;M;.;.;.;.;.

PhyloP100

6.7

PROVEAN

Pathogenic

-4.9

.;.;.;D;.;.;.;.;.;.

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

.;.;.;D;.;.;.;.;.;.

Sift4G

Uncertain

0.0040

D;D;D;T;T;D;T;T;D;.

Polyphen

1.0, 0.99

.;.;.;D;D;D;.;.;.;.

Vest4

0.94

MutPred

0.75

.;.;.;Gain of ubiquitination at M227 (P = 0.0247);Gain of ubiquitination at M227 (P = 0.0247);.;.;.;.;.;

MVP

0.82

MPC

0.55

ClinPred

0.92

GERP RS

4.9

Varity_R

0.96

gMVP

0.92

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over