rs561425038

Variant names:

• chr17-35119613-T-A
• rs561425038
• NM_002878.4:c.1A>T

Your query was ambiguous. Multiple possible variants found:

• chr17-35119613-T-A
• chr17-35119613-T-C
• chr17-35119613-T-G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The NM_002878.4(RAD51D):​c.1A>T​(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.00000206 in 1,458,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RAD51D NM_002878.4 initiator_codon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:4
• Conservation: PhyloP100: 5.06
• Publications: 12 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: Pathogenic. The variant received 13 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 20 pathogenic variants. Next in-frame start position is after 16 codons. Genomic position: 35119568. Lost 0.047 part of the original CDS.
• PS1: Another start lost variant in NM_002878.4 (RAD51D) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-35119613-T-A is Pathogenic according to our data. Variant chr17-35119613-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 419798.

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.1A>T	p.Met1?	initiator_codon	Exon 1 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 10	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.1A>T	p.Met1?	initiator_codon	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.1A>T	p.Met1?	initiator_codon	Exon 1 of 10	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000468273.3	O75771-4
	RAD51D	ENST00000335858.11	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 7	ENSP00000338408.6	O75771-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458698 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725818

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

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: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50380

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.024
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.56	T
PhyloP100		5.1
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.090	B
Vest4		0.95
MutPred		0.99		Loss of sheet (P = 0.0054)
MVP		0.80
ClinPred		0.99	D
GERP RS		4.5
PromoterAI		-0.061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.95
gMVP		0.57
Mutation Taster		=3/197	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: rs561425038; hg19: chr17-33446632;