rs140317560

Positions:

chr17-35118618-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_002878.4(RAD51D):c.146C>T(p.Ala49Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000203 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense, splice_region

Scores

Splicing: ADA: 0.9884

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:12

Conservation

PhyloP100: 5.18

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 Benign. Variant got -8 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 17-35118618-G-A is Benign according to our data. Variant chr17-35118618-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127883.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=3, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00106 (161/152348) while in subpopulation AFR AF= 0.00378 (157/41580). AF 95% confidence interval is 0.00329. There are 0 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 161 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4 linkuse as main transcript	c.146C>T	p.Ala49Val	missense_variant, splice_region_variant	3/10	ENST00000345365.11	NP_002869.3
RAD51L3-RFFL	NR_037714.1 linkuse as main transcript	n.232+2673C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 linkuse as main transcript	c.146C>T	p.Ala49Val	missense_variant, splice_region_variant	3/10	1	NM_002878.4	ENSP00000338790	P1	O75771-1

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

162

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00379

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000311

AC:

AN:

251124

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.00439

Gnomad AMR exome

AF:

0.000202

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:

0.000114

AC:

166

AN:

1461352

Hom.:

Cov.:

AF XY:

0.0000935

AC XY:

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.00421

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.00106

AC:

161

AN:

152348

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00378

Gnomad4 AMR

AF:

0.000261

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:

0.000210

Hom.:

Bravo

AF:

0.00124

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000371

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 17, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2017	Variant summary: The RAD51D c.146C>T (p.Ala49Val) variant involves the alteration of a conserved nucleotide and 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome. The variant of interest is also located at the second 5' position of exon 3 and thus could affect splicing, which 3/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. However, these predictions have yet to be confirmed by functional studies. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 45/120782 (1/2683), predominantly in the African cohort, 43/10248 (1/238), which exceeds the estimated maximal expected allele frequency for a pathogenic RAD51D variant of 1/8000. Therefore, suggesting this variant is likely a benign polymorphism found primarily in population(s) of African origin. A publication cites the variant in one affected individual diagnosed with Lynch syndrome-associated cancer and/or polyps, however, with limited information (ie, lack of cosegregation data). In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/uncertain significance. Taken together, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2021	This variant is associated with the following publications: (PMID: 25980754, 27720647, 25186627) -

Breast-ovarian cancer, familial, susceptibility to, 4

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 06, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 02, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 04, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2015	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 28, 2022	- -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

T;T;T

Eigen

Benign

0.036

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

.;D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.2

L;L;.

MutationTaster

Benign

1.0

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

PROVEAN

Benign

-0.95

N;.;.

REVEL

Benign

0.17

Sift

Benign

0.14

T;.;.

Sift4G

Benign

0.81

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.38

MVP

0.67

ClinPred

0.035

GERP RS

4.8

Varity_R

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

0.060

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