rs140848654

Variant names:

• chr17-35101231-G-A
• rs140848654
• NM_002878.4:c.873C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-35101231-G-A
• chr17-35101231-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002878.4(RAD51D):​c.873C>T​(p.Arg291Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,614,178 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (4 hom.)
• Consequence: RAD51D NM_002878.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0580
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-35101231-G-A is Benign according to our data. Variant chr17-35101231-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.058 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00365 (556/152298) while in subpopulation AFR AF = 0.0121 (503/41568). AF 95% confidence interval is 0.0112. There are 4 homozygotes in GnomAd4. There are 253 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 556 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.873C>T	p.Arg291Arg	synonymous	Exon 9 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.933C>T	p.Arg311Arg	synonymous	Exon 9 of 10	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.537C>T	p.Arg179Arg	synonymous	Exon 6 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.873C>T	p.Arg291Arg	synonymous	Exon 9 of 10	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.738C>T	p.Arg246Arg	synonymous	Exon 8 of 9	ENSP00000468273.3	O75771-4
	ENSG00000267618	ENST00000593039.5	TSL:2	c.396C>T	p.Arg132Arg	synonymous	Exon 5 of 7	ENSP00000466834.1	K7EN88

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 556 AN: 152180 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

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: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000879 AC: 221 AN: 251424 AF XY: 0.000655

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000324 AC: 473 AN: 1461880 Hom.: 4 Cov.: 31 AF XY: 0.000272 AC XY: 198 AN XY: 727236

African (AFR) AF: 0.0120 AC: 403 AN: 33480

American (AMR) AF: 0.000738 AC: 33 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112008

Other (OTH) AF: 0.000546 AC: 33 AN: 60394

GnomAD4 genome AF: 0.00365 AC: 556 AN: 152298 Hom.: 4 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74472

African (AFR) AF: 0.0121 AC: 503 AN: 41568

American (AMR) AF: 0.00288 AC: 44 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00432

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.2
DANN	Benign	0.72
PhyloP100		-0.058
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs140848654; hg19: chr17-33428250; COSMIC: COSV104653528;