NM_002878.4:c.577-2A>G

Variant names:

• chr17-35103546-T-C
• rs1555567649
• NM_002878.4:c.577-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_002878.4(RAD51D):​c.577-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000667145: Internal and published RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51D NM_002878.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.41
• 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: Pathogenic. The variant received 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.1, offset of 16, new splice context is: tcgggtgactggttcttcAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000667145: Internal and published RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Bueno-Martínez E et al. Cancers (Basel), 2021 Jun;13).; SCV001353496: RNA studies indicate this variant results in multiple aberrantly spliced products and is expected to result in loss of RAD51D function (PMID: 34200360).; SCV000889828: "In addition, this variant alters RAD51D RNA splicing in a minigene assay." PMID: 34200360 (2021); SCV005373329: Canonical splice site variant predicted to result in a null allele and demonstrated to result in multiple aberrant transcripts in a minigene assay in a gene for which loss of function is a known mechanism of disease (PMID: 34200360); SCV001205046: Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 34200360).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-35103546-T-C is Pathogenic according to our data. Variant chr17-35103546-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 482184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.577-2A>G		splice_acceptor intron	N/A	NP_002869.3
	RAD51D	NM_001142571.2		c.637-2A>G		splice_acceptor intron	N/A	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.241-2A>G		splice_acceptor 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.577-2A>G		splice_acceptor intron	N/A	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.442-2A>G		splice_acceptor intron	N/A	ENSP00000468273.3	O75771-4
	ENSG00000267618	ENST00000593039.5	TSL:2	c.100-2A>G		splice_acceptor intron	N/A	ENSP00000466834.1	K7EN88

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	32
DANN	Benign	0.90
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		4.4
GERP RS		4.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.56		Position offset: -18
DS_AL_spliceai		0.99		Position offset: -2

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

Other links and lift over

dbSNP: rs1555567649; hg19: chr17-33430565;