17-35106468-C-T

Position:

• chr17-35106468-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002878.4(RAD51D):​c.494G>A​(p.Arg165Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,611,192 control chromosomes in the GnomAD database, including 17,336 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1455 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15881 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.18

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]

ENSG00000267618 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022848845).
• BP6: Variant 17-35106468-C-T is Benign according to our data. Variant chr17-35106468-C-T is described in ClinVar as [Benign]. Clinvar id is 142159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-35106468-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51D	NM_002878.4	c.494G>A	p.Arg165Gln	missense_variant	6/10	ENST00000345365.11	NP_002869.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11	c.494G>A	p.Arg165Gln	missense_variant	6/10	1	NM_002878.4	ENSP00000338790.6
ENSG00000267618	ENST00000593039.5	c.17G>A	p.Arg6Gln	missense_variant	2/7	2		ENSP00000466834.1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18421 AN: 152092 Hom.: 1452 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.0458

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.156 AC: 38415 AN: 247030 Hom.: 3695 AF XY: 0.154 AC XY: 20565 AN XY: 133538

Gnomad AFR exome AF: 0.0296

Gnomad AMR exome AF: 0.295

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.0455

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.141 AC: 205147 AN: 1458982 Hom.: 15881 Cov.: 32 AF XY: 0.141 AC XY: 102408 AN XY: 725640

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.285

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.0429

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.166

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.121 AC: 18427 AN: 152210 Hom.: 1455 Cov.: 32 AF XY: 0.125 AC XY: 9284 AN XY: 74424

Gnomad4 AFR AF: 0.0335

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.0459

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.144

Gnomad4 OTH AF: 0.117

Alfa AF: 0.138 Hom.: 4163

Bravo AF: 0.120

TwinsUK AF: 0.143 AC: 531

ALSPAC AF: 0.131 AC: 504

ESP6500AA AF: 0.0368 AC: 162

ESP6500EA AF: 0.143 AC: 1227

ExAC AF: 0.148 AC: 17916

Asia WGS AF: 0.0980 AC: 343 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4 Benign:5

Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 2023	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28202063) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 18, 2019	This alteration is classified as 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, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.074	.;.;T;T;.;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.65	T;T;.;T;T;T;T;T
MetaRNN	Benign	0.0023	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	.;.;N;N;.;.;.;.
PROVEAN	Benign	1.6	.;.;N;D;.;.;.;.
REVEL	Benign	0.13
Sift	Benign	1.0	.;.;T;D;.;.;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;.
Polyphen		0.0, 0.0080	.;.;B;B;B;.;.;.
Vest4		0.080
MPC		0.41
ClinPred		0.0074	T
GERP RS		0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.051

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

LitVar

Other links and lift over

dbSNP: rs4796033; hg19: chr17-33433487; COSMIC: COSV104653496; COSMIC: COSV104653496;