17-35119588-C-G

Variant names:

• chr17-35119588-C-G
• rs140825795
• NM_002878.4:c.26G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_002878.4(RAD51D):​c.26G>C​(p.Cys9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000656 in 1,612,440 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C9Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (1 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:9
• Conservation: PhyloP100: 3.45
• Publications: 21 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23021111).
• BP6: Variant 17-35119588-C-G is Benign according to our data. Variant chr17-35119588-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127886.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000675 (986/1460118) while in subpopulation NFE AF = 0.000831 (924/1111920). AF 95% confidence interval is 0.000787. There are 1 homozygotes in GnomAdExome4. There are 499 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 72 AD gene.

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.26G>C	p.Cys9Ser	missense	Exon 1 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.26G>C	p.Cys9Ser	missense	Exon 1 of 10	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.26G>C	p.Cys9Ser	missense	Exon 1 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.26G>C	p.Cys9Ser	missense	Exon 1 of 10	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.26G>C	p.Cys9Ser	missense	Exon 1 of 9	ENSP00000468273.3	O75771-4
	RAD51D	ENST00000335858.11	TSL:1	c.26G>C	p.Cys9Ser	missense	Exon 1 of 7	ENSP00000338408.6	O75771-3

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000372 AC: 92 AN: 247570 AF XY: 0.000410

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000489

Gnomad NFE exome AF: 0.000674

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000675 AC: 986 AN: 1460118 Hom.: 1 Cov.: 31 AF XY: 0.000687 AC XY: 499 AN XY: 726452

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.000291 AC: 13 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000831 AC: 924 AN: 1111920

Other (OTH) AF: 0.000762 AC: 46 AN: 60364

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74484

African (AFR) AF: 0.000241 AC: 10 AN: 41570

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000546 Hom.: 1

Bravo AF: 0.000423

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000346 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	Breast-ovarian cancer, familial, susceptibility to, 4 (5)
-	3	2	not provided (5)
-	1	2	Hereditary cancer-predisposing syndrome (3)
-	2	1	not specified (3)
-	1	-	Breast and/or ovarian cancer (1)
-	-	1	Hereditary cancer (1)
-	1	-	Malignant tumor of breast (1)
-	-	1	RAD51D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.4
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.95	P
Vest4		0.76
MutPred		0.75		Gain of disorder (P = 0.0024)
MVP		0.90
MPC		0.37
ClinPred		0.12	T
GERP RS		4.5
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.91
gMVP		0.76
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs140825795; hg19: chr17-33446607;