17-35106468-C-T

Variant names:

• chr17-35106468-C-T
• rs4796033
• NM_002878.4:c.494G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165W) has been classified as Uncertain significance.

• 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:13
• Conservation: PhyloP100: 1.18
• Publications: 53 publications found

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):

• RAD51D-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000267618 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 142159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002878.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51D	NM_002878.4	MANE Select	c.494G>A	p.Arg165Gln	missense	Exon 6 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.554G>A	p.Arg185Gln	missense	Exon 6 of 10	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.158G>A	p.Arg53Gln	missense	Exon 3 of 7	NP_598332.1	O75771-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51D	ENST00000345365.11	TSL:1 MANE Select	c.494G>A	p.Arg165Gln	missense	Exon 6 of 10	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.359G>A	p.Arg120Gln	missense	Exon 5 of 9	ENSP00000468273.3	O75771-4
	ENSG00000267618	ENST00000593039.5	TSL:2	c.17G>A	p.Arg6Gln	missense	Exon 2 of 7	ENSP00000466834.1	K7EN88

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

GnomAD2 exomes AF: 0.156 AC: 38415 AN: 247030 AF XY: 0.154

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 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

African (AFR) AF: 0.0265 AC: 887 AN: 33438

American (AMR) AF: 0.285 AC: 12638 AN: 44354

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 5050 AN: 25976

East Asian (EAS) AF: 0.0429 AC: 1702 AN: 39692

South Asian (SAS) AF: 0.163 AC: 14025 AN: 85796

European-Finnish (FIN) AF: 0.166 AC: 8846 AN: 53290

Middle Eastern (MID) AF: 0.129 AC: 744 AN: 5758

European-Non Finnish (NFE) AF: 0.138 AC: 153134 AN: 1110356

Other (OTH) AF: 0.135 AC: 8121 AN: 60322

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

African (AFR) AF: 0.0335 AC: 1393 AN: 41536

American (AMR) AF: 0.217 AC: 3326 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 712 AN: 3470

East Asian (EAS) AF: 0.0459 AC: 238 AN: 5184

South Asian (SAS) AF: 0.144 AC: 696 AN: 4818

European-Finnish (FIN) AF: 0.178 AC: 1886 AN: 10600

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9794 AN: 67994

Other (OTH) AF: 0.117 AC: 247 AN: 2110

Alfa AF: 0.136 Hom.: 7501

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Breast-ovarian cancer, familial, susceptibility to, 4 (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		1.2
PROVEAN	Benign	1.6	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	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
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

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