17-35101021-C-T

Variant names:

• chr17-35101021-C-T
• rs115031549
• NM_002878.4:c.919G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002878.4(RAD51D):​c.919G>A​(p.Glu307Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,613,792 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. E307A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (2 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 2.03
• Publications: 3 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005851954).
• BP6: Variant 17-35101021-C-T is Benign according to our data. Variant chr17-35101021-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127895.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000762 (116/152330) while in subpopulation AFR AF = 0.00272 (113/41586). AF 95% confidence interval is 0.00231. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 116 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.919G>A	p.Glu307Lys	missense	Exon 10 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.979G>A	p.Glu327Lys	missense	Exon 10 of 10	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.583G>A	p.Glu195Lys	missense	Exon 7 of 7	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.919G>A	p.Glu307Lys	missense	Exon 10 of 10	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.784G>A	p.Glu262Lys	missense	Exon 9 of 9	ENSP00000468273.3	O75771-4
	RAD51D	ENST00000335858.11	TSL:1	c.583G>A	p.Glu195Lys	missense	Exon 7 of 7	ENSP00000338408.6	O75771-3

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 116 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000227 AC: 57 AN: 251486 AF XY: 0.000184

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1461462 Hom.: 2 Cov.: 30 AF XY: 0.0000839 AC XY: 61 AN XY: 727058

African (AFR) AF: 0.00311 AC: 104 AN: 33468

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111624

Other (OTH) AF: 0.000166 AC: 10 AN: 60378

GnomAD4 genome AF: 0.000762 AC: 116 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74486

African (AFR) AF: 0.00272 AC: 113 AN: 41586

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000375 Hom.: 0

Bravo AF: 0.000899

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000214 AC: 26

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Breast-ovarian cancer, familial, susceptibility to, 4 (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary cancer (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	not specified (1)
-	-	1	RAD51D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		2.0
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.15
Sift	Benign	0.18	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.18
MVP		0.61
MPC		0.095
ClinPred		0.022	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.59
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs115031549; hg19: chr17-33428040;