rs1060502951

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_002878.4(RAD51D):c.301G>C(p.Glu101Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000575 in 1,565,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 5.55

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 links:

RAD51L3-RFFL (HGNC:):

RAD51L3-RFFL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51D	NM_002878.4 linkuse as main transcript	c.301G>C	p.Glu101Gln	missense_variant	4/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1 linkuse as main transcript	n.233-929G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11 linkuse as main transcript	c.301G>C	p.Glu101Gln	missense_variant	4/10	1	NM_002878.4	P1	O75771-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251354

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000495

AC:

AN:

1413212

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

705442

show subpopulations

Gnomad4 AFR exome

AF:

0.000186

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:

9.37e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 01, 2023	The p.E101Q variant (also known as c.301G>C), located in coding exon 4 of the RAD51D gene, results from a G to C substitution at nucleotide position 301. The glutamic acid at codon 101 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2023	This missense variant replaces glutamic acid with glutamine at codon 101 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RAD51D-related disorders in the literature. This variant has been identified in 2/251354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Breast-ovarian cancer, familial, susceptibility to, 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 07, 2023	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. 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 not expected to disrupt RAD51D protein function. ClinVar contains an entry for this variant (Variation ID: 410544). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 101 of the RAD51D protein (p.Glu101Gln). -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 14, 2023	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.18

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.15

T;T;.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.038

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.5

L;L;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PROVEAN

Benign

-1.5

N;.;.;.

REVEL

Benign

0.19

Sift

Benign

0.12

T;.;.;.

Sift4G

Benign

0.20

T;T;T;.

Polyphen

0.93

P;P;.;.

Vest4

0.66

MutPred

0.45

Loss of disorder (P = 0.148);Loss of disorder (P = 0.148);.;.;

MVP

0.87

MPC

0.41

ClinPred

0.73

GERP RS

4.7

Varity_R

0.51

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

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

Other links and lift over