rs1403784434

Variant names:

• chr17-35101038-T-A
• rs1403784434
• NM_002878.4:c.904-2A>T

Your query was ambiguous. Multiple possible variants found:

• chr17-35101038-T-A
• chr17-35101038-T-G
• chr17-35101038-T-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 20P and 4B. PVS1 PS3 PP5_Very_Strong BS2

The NM_002878.4(RAD51D):​c.904-2A>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000144 in 1,461,056 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000651794: Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a new termination codon (Invitae)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RAD51D NM_002878.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1
• Conservation: PhyloP100: 4.50
• Publications: 6 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000267618 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000651794: Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a new termination codon (Invitae).; SCV000674697: RNA analyses have shown that this alteration leads to an aberrant splicing by activation of cryptic acceptor site (Casadei S et al. Proc. Natl. Acad. Sci. U.S.A., 2019 Dec; Ambry internal data).
• PP5: Variant 17-35101038-T-A is Pathogenic according to our data. Variant chr17-35101038-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 472631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 21 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.904-2A>T		splice_acceptor intron	N/A	NP_002869.3
	RAD51D	NM_001142571.2		c.964-2A>T		splice_acceptor intron	N/A	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.568-2A>T		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.904-2A>T		splice_acceptor intron	N/A	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.769-2A>T		splice_acceptor intron	N/A	ENSP00000468273.3	O75771-4
	ENSG00000267618	ENST00000593039.5	TSL:2	c.426+163A>T		intron	N/A	ENSP00000466834.1	K7EN88

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251488 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461056 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726906

African (AFR) AF: 0.00 AC: 0 AN: 33446

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000529 AC: 21 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111278

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Pathogenic	0.86
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
Splicevardb		3.0
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.57		Position offset: -9
DS_AL_spliceai		0.65		Position offset: -2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1403784434;

hg19: chr17-33428057;