rs1335185570

Variant names:

• chr17-35116904-G-GA
• rs1335185570
• NM_002878.4:c.263+1596dupT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 8P and 6B. PVS1 BP6_Moderate BS2

The NM_001142571.2(RAD51D):​c.277dupT​(p.Ser93PhefsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,601,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: RAD51D NM_001142571.2 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0950
• 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):

• 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: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 17-35116904-G-GA is Benign according to our data. Variant chr17-35116904-G-GA is described in ClinVar as Likely_benign. ClinVar VariationId is 492417.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 37 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142571.2. 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.263+1596dupT		intron	N/A	NP_002869.3
	RAD51D	NM_001142571.2		c.277dupT	p.Ser93PhefsTer7	frameshift	Exon 3 of 10	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.144+2206dupT		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.263+1596dupT		intron	N/A	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.263+1596dupT		intron	N/A	ENSP00000468273.3	O75771-4
	ENSG00000267618	ENST00000593039.5	TSL:2	c.3+4386dupT		intron	N/A	ENSP00000466834.1	K7EN88

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000440 AC: 1 AN: 227284 AF XY: 0.00000812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000994

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000255 AC: 37 AN: 1449274 Hom.: 0 Cov.: 31 AF XY: 0.0000195 AC XY: 14 AN XY: 719732

African (AFR) AF: 0.00 AC: 0 AN: 33080

American (AMR) AF: 0.00 AC: 0 AN: 42642

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39122

South Asian (SAS) AF: 0.00 AC: 0 AN: 84270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000326 AC: 36 AN: 1105776

Other (OTH) AF: 0.0000167 AC: 1 AN: 59990

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.095
Mutation Taster		=14/186	disease causing (fs/PTC)

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: rs1335185570; hg19: chr17-33443923;