rs33929366

Variant names:

• chr14-67887196-T-G
• rs33929366
• NM_133510.4:c.748T>G
• RAD51B p.Ser250Ala

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_133510.4(RAD51B):​c.748T>G​(p.Ser250Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00156 in 1,606,150 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S250S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0084 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (21 hom.)
• Consequence: RAD51B NM_133510.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.06
• Publications: 6 publications found

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]

RAD51B Gene-Disease associations (from GenCC):

• primary ovarian failure

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065518618).
• BP6: Variant 14-67887196-T-G is Benign according to our data. Variant chr14-67887196-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1678953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00838 (1277/152300) while in subpopulation AFR AF = 0.0298 (1239/41574). AF 95% confidence interval is 0.0284. There are 14 homozygotes in GnomAd4. There are 602 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133510.4. 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
	RAD51B	NM_133510.4	MANE Select	c.748T>G	p.Ser250Ala	missense	Exon 7 of 11	NP_598194.1	O15315-2
	RAD51B	NM_001321821.2		c.748T>G	p.Ser250Ala	missense	Exon 7 of 11	NP_001308750.1	C9JYJ0
	RAD51B	NM_133509.5		c.748T>G	p.Ser250Ala	missense	Exon 7 of 11	NP_598193.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51B	ENST00000471583.6	TSL:1 MANE Select	c.748T>G	p.Ser250Ala	missense	Exon 7 of 11	ENSP00000418859.1	O15315-2
	RAD51B	ENST00000487861.5	TSL:1	c.748T>G	p.Ser250Ala	missense	Exon 7 of 11	ENSP00000419881.1	C9JYJ0
	RAD51B	ENST00000487270.5	TSL:1	c.748T>G	p.Ser250Ala	missense	Exon 7 of 11	ENSP00000419471.1	O15315-3

Frequencies

GnomAD3 genomes AF: 0.00835 AC: 1270 AN: 152182 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

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: 0.0000441

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00216 AC: 531 AN: 245786 AF XY: 0.00169

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.00123

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: 0.00133

GnomAD4 exome AF: 0.000841 AC: 1223 AN: 1453850 Hom.: 21 Cov.: 30 AF XY: 0.000780 AC XY: 564 AN XY: 722954

African (AFR) AF: 0.0306 AC: 1014 AN: 33134

American (AMR) AF: 0.00135 AC: 59 AN: 43822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.000107 AC: 9 AN: 83872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5742

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1108302

Other (OTH) AF: 0.00186 AC: 112 AN: 60096

GnomAD4 genome AF: 0.00838 AC: 1277 AN: 152300 Hom.: 14 Cov.: 32 AF XY: 0.00808 AC XY: 602 AN XY: 74480

African (AFR) AF: 0.0298 AC: 1239 AN: 41574

American (AMR) AF: 0.00144 AC: 22 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00419 Hom.: 12

Bravo AF: 0.00925

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.017	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.059
Sift	Benign	0.44	T
Sift4G	Benign	0.16	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.41
Mutation Taster		=99/1	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs33929366;

hg19: chr14-68353913;

COSMIC: COSV104699691;