rs544654228

Variant names:

• chr17-35106469-G-A
• rs544654228
• NM_002878.4:c.493C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-35106469-G-A
• chr17-35106469-G-C
• chr17-35106469-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002878.4(RAD51D):​c.493C>T​(p.Arg165Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000688 in 1,612,350 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R165Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:15 B:1
• Conservation: PhyloP100: 4.82
• Publications: 7 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 8 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.493C>T	p.Arg165Trp	missense	Exon 6 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.553C>T	p.Arg185Trp	missense	Exon 6 of 10	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.157C>T	p.Arg53Trp	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.493C>T	p.Arg165Trp	missense	Exon 6 of 10	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.358C>T	p.Arg120Trp	missense	Exon 5 of 9	ENSP00000468273.3	O75771-4
	ENSG00000267618	ENST00000593039.5	TSL:2	c.16C>T	p.Arg6Trp	missense	Exon 2 of 7	ENSP00000466834.1	K7EN88

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000404 AC: 10 AN: 247668 AF XY: 0.0000373

Gnomad AFR exome AF: 0.0000641

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000536

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000705 AC: 103 AN: 1460030 Hom.: 0 Cov.: 31 AF XY: 0.0000730 AC XY: 53 AN XY: 726106

African (AFR) AF: 0.000120 AC: 4 AN: 33448

American (AMR) AF: 0.0000225 AC: 1 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000774 AC: 86 AN: 1111164

Other (OTH) AF: 0.000116 AC: 7 AN: 60342

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74476

African (AFR) AF: 0.0000722 AC: 3 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000580 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	-	Hereditary cancer-predisposing syndrome (5)
-	3	1	Breast-ovarian cancer, familial, susceptibility to, 4 (4)
-	3	-	not provided (3)
-	2	-	not specified (2)
-	1	-	Breast and/or ovarian cancer (1)
-	1	-	Familial ovarian cancer (1)
1	-	-	Lynch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	33
DANN	Benign	0.97
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.8
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.96	D
Vest4		0.28
MutPred		0.53		Loss of disorder (P = 0.0172)
MVP		0.90
MPC		0.37
ClinPred		0.46	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.30
Mutation Taster		=56/44	disease causing (ClinVar)

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: rs544654228; hg19: chr17-33433488; COSMIC: COSV105193567; COSMIC: COSV105193567;