rs753393344

Positions:

• chr14-67865142-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_133510.4(RAD51B):​c.452+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000523 in 1,586,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: RAD51B NM_133510.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9534
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.990

Genes affected

RAD51B (HGNC:9822): (RAD51 paralog B) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are evolutionarily conserved proteins essential for DNA repair by homologous recombination. This protein has been shown to form a stable heterodimer with the family member RAD51C, which further interacts with the other family members, such as RAD51, XRCC2, and XRCC3. Overexpression of this gene was found to cause cell cycle G1 delay and cell apoptosis, which suggested a role of this protein in sensing DNA damage. Rearrangements between this locus and high mobility group AT-hook 2 (HMGA2, GeneID 8091) have been observed in uterine leiomyomata. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 14-67865142-A-G is Benign according to our data. Variant chr14-67865142-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224592.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51B	NM_133510.4	c.452+3A>G		splice_donor_region_variant, intron_variant		ENST00000471583.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51B	ENST00000471583.6	c.452+3A>G		splice_donor_region_variant, intron_variant		1	NM_133510.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000462 AC: 7 AN: 151482 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000864 AC: 20 AN: 231560 Hom.: 0 AF XY: 0.0000797 AC XY: 10 AN XY: 125540

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000272

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000297

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000652

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000530 AC: 76 AN: 1435296 Hom.: 0 Cov.: 33 AF XY: 0.0000490 AC XY: 35 AN XY: 713890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000179

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.0000445

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.0000462 AC: 7 AN: 151482 Hom.: 0 Cov.: 27 AF XY: 0.0000406 AC XY: 3 AN XY: 73968

Gnomad4 AFR AF: 0.0000485

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000973 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 26, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Oct 22, 2019

This variant was predicted to disrupt a splice donor site, resulting in skipping of exon 5 and production of abnormally short protein. This variant has been reported in a patient with a family history of breast cancer and loss of RAD51B expression (Golmard 2013). However, this variant is found in approximately 1/6000 individuals in the population. It has also been detected in three women over age 70 with no history of cancer (https://whi.color.com/) and 20 individuals in an unaffected control population (gnomAD). The presence of this variant at this frequency in unaffected women indicates that it does not substantially increase cancer risk. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Pathogenic	26
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs753393344; hg19: chr14-68331859;