14-67825470-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_133510.4(RAD51B):c.91T>C(p.Leu31=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,608,320 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: RAD51B NM_133510.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0880

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 14-67825470-T-C is Benign according to our data. Variant chr14-67825470-T-C is described in ClinVar as [Benign]. Clinvar id is 714335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.088 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1707/152332) while in subpopulation AFR AF= 0.0383 (1591/41574). AF 95% confidence interval is 0.0367. There are 41 homozygotes in gnomad4. There are 769 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1707 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51B	NM_133510.4	c.91T>C	p.Leu31=	synonymous_variant	3/11	ENST00000471583.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51B	ENST00000471583.6	c.91T>C	p.Leu31=	synonymous_variant	3/11	1	NM_133510.4	P4

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1707 AN: 152214 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00267 AC: 666 AN: 249388 Hom.: 13 AF XY: 0.00182 AC XY: 246 AN XY: 134804

Gnomad AFR exome AF: 0.0359

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000997

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00109 AC: 1590 AN: 1455988 Hom.: 28 Cov.: 29 AF XY: 0.000919 AC XY: 666 AN XY: 724530

Gnomad4 AFR exome AF: 0.0362

Gnomad4 AMR exome AF: 0.00182

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000175

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.00284

GnomAD4 genome AF: 0.0112 AC: 1707 AN: 152332 Hom.: 41 Cov.: 32 AF XY: 0.0103 AC XY: 769 AN XY: 74498

Gnomad4 AFR AF: 0.0383

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00656 Hom.: 8

Bravo AF: 0.0127

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2018

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	5.7
Dann	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs114131734; hg19: chr14-68292187;