rs28363284

Variant names:

• chr17-35103294-T-C
• rs28363284
• NM_002878.4:c.698A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-35103294-T-C
• chr17-35103294-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002878.4(RAD51D):​c.698A>G​(p.Glu233Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,611,638 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E233D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 32)
  • Exomes 𝑓: 0.017 (285 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 3.00
• Publications: 34 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=0.012577295).
• BP6: Variant 17-35103294-T-C is Benign according to our data. Variant chr17-35103294-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0109 (1660/152080) while in subpopulation NFE AF = 0.0192 (1303/67990). AF 95% confidence interval is 0.0183. There are 12 homozygotes in GnomAd4. There are 749 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1660 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.698A>G	p.Glu233Gly	missense	Exon 8 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.758A>G	p.Glu253Gly	missense	Exon 8 of 10	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.362A>G	p.Glu121Gly	missense	Exon 5 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.698A>G	p.Glu233Gly	missense	Exon 8 of 10	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.563A>G	p.Glu188Gly	missense	Exon 7 of 9	ENSP00000468273.3	O75771-4
	ENSG00000267618	ENST00000593039.5	TSL:2	c.221A>G	p.Glu74Gly	missense	Exon 4 of 7	ENSP00000466834.1	K7EN88

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1661 AN: 151962 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00322

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00865

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00966 AC: 2374 AN: 245702 AF XY: 0.00973

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.00728

Gnomad ASJ exome AF: 0.00172

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00119

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0174 AC: 25453 AN: 1459558 Hom.: 285 Cov.: 32 AF XY: 0.0169 AC XY: 12235 AN XY: 725816

African (AFR) AF: 0.00302 AC: 101 AN: 33462

American (AMR) AF: 0.00778 AC: 345 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 45 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00358 AC: 307 AN: 85648

European-Finnish (FIN) AF: 0.00163 AC: 87 AN: 53240

Middle Eastern (MID) AF: 0.00699 AC: 40 AN: 5724

European-Non Finnish (NFE) AF: 0.0212 AC: 23600 AN: 1111122

Other (OTH) AF: 0.0154 AC: 928 AN: 60296

GnomAD4 genome AF: 0.0109 AC: 1660 AN: 152080 Hom.: 12 Cov.: 32 AF XY: 0.0101 AC XY: 749 AN XY: 74352

African (AFR) AF: 0.00321 AC: 133 AN: 41460

American (AMR) AF: 0.00864 AC: 132 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3462

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4828

European-Finnish (FIN) AF: 0.00180 AC: 19 AN: 10576

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0192 AC: 1303 AN: 67990

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.0150 Hom.: 75

Bravo AF: 0.0110

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0169 AC: 145

ExAC AF: 0.00874 AC: 1061

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Breast-ovarian cancer, familial, susceptibility to, 4 (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.0
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.19
Sift	Benign	0.065	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.97	D
Vest4		0.63
MVP		0.91
MPC		0.42
ClinPred		0.022	T
GERP RS		4.9
Varity_R		0.47
gMVP		0.65
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.090		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: rs28363284; hg19: chr17-33430313; COSMIC: COSV99047024; COSMIC: COSV99047024;