17-35119124-C-G

Variant names:

• chr17-35119124-C-G
• rs374730714
• NM_002878.4:c.131G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002878.4(RAD51D):​c.131G>C​(p.Gly44Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G44C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RAD51D NM_002878.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.976
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33401668).
• BS2: High AC in GnomAdExome4 at 17 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.131G>C	p.Gly44Ala	missense	Exon 2 of 10	NP_002869.3
	RAD51D	NM_001142571.2		c.131G>C	p.Gly44Ala	missense	Exon 2 of 10	NP_001136043.1	O75771-8
	RAD51D	NM_133629.3		c.131G>C	p.Gly44Ala	missense	Exon 2 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.131G>C	p.Gly44Ala	missense	Exon 2 of 10	ENSP00000338790.6	O75771-1
	RAD51D	ENST00000586186.3	TSL:1	c.131G>C	p.Gly44Ala	missense	Exon 2 of 9	ENSP00000468273.3	O75771-4
	RAD51D	ENST00000335858.11	TSL:1	c.131G>C	p.Gly44Ala	missense	Exon 2 of 7	ENSP00000338408.6	O75771-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461416 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727036

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111592

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.98
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.065
Sift	Benign	0.26	T
Sift4G	Benign	0.072	T
Polyphen		0.38	B
Vest4		0.25
MutPred		0.58		Loss of loop (P = 0.0145)
MVP		0.89
MPC		0.092
ClinPred		0.56	D
GERP RS		4.0
PromoterAI		0.0053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.25
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs374730714; hg19: chr17-33446143;