chr17-35107034-C-G

Variant names:

• chr17-35107034-C-G
• rs147264215
• NM_002878.4:c.434G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002878.4(RAD51D):​c.434G>C​(p.Arg145Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R145C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.96
• Publications: 0 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):

• breast-ovarian cancer, familial, susceptibility to, 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000267618 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51D	NM_002878.4	MANE Select	c.434G>C	p.Arg145Pro	missense	Exon 5 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.494G>C	p.Arg165Pro	missense	Exon 5 of 10	NP_001136043.1
	RAD51D	NR_037711.2		n.460G>C		non_coding_transcript_exon	Exon 4 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51D	ENST00000345365.11	TSL:1 MANE Select	c.434G>C	p.Arg145Pro	missense	Exon 5 of 10	ENSP00000338790.6
	RAD51D	ENST00000585343.5	TSL:1	n.*256G>C		non_coding_transcript_exon	Exon 5 of 6	ENSP00000465007.1
	RAD51D	ENST00000586044.5	TSL:1	n.*165G>C		non_coding_transcript_exon	Exon 4 of 9	ENSP00000465584.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Benign	0.94
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		6.0
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.74		Gain of glycosylation at R145 (P = 0.1463)
MVP		0.97
MPC		0.55
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs147264215; hg19: chr17-33434053;