rs1555568469

Variant names:

• chr17-35107366-C-G
• rs1555568469
• NM_002878.4:c.345G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-35107366-C-G
• chr17-35107366-C-T
• chr17-35107366-C-A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_002878.4(RAD51D):​c.345G>C​(p.Gln115His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000144 in 1,393,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. Q115L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RAD51D NM_002878.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 O:1
• Conservation: PhyloP100: 5.48
• Publications: 1 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_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-35107366-C-G is Pathogenic according to our data. Variant chr17-35107366-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 643598.

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.345G>C	p.Gln115His	missense splice_region	Exon 4 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.405G>C	p.Gln135His	missense splice_region	Exon 4 of 10	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.145-885G>C		intron	N/A	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.345G>C	p.Gln115His	missense splice_region	Exon 4 of 10	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.345G>C	p.Gln115His	missense splice_region	Exon 4 of 9	ENSP00000468273.3	O75771-4
	ENSG00000267618	ENST00000593039.5	TSL:2	c.4-885G>C		intron	N/A	ENSP00000466834.1	K7EN88

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1393522 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 696360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31836

American (AMR) AF: 0.00 AC: 0 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25756

East Asian (EAS) AF: 0.00 AC: 0 AN: 39342

South Asian (SAS) AF: 0.00 AC: 0 AN: 84840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1049928

Other (OTH) AF: 0.00 AC: 0 AN: 58174

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Breast-ovarian cancer, familial, susceptibility to, 4 (3)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.5
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.80		Gain of disorder (P = 0.1154)
MVP		0.99
MPC		0.45
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.92
gMVP		0.83
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555568469; hg19: chr17-33434385;