rs28908168

Variant names:

• chr14-67887067-G-T
• rs28908168
• NM_133510.4:c.619G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-67887067-G-T
• chr14-67887067-G-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_133510.4(RAD51B):​c.619G>T​(p.Val207Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,563,044 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (8 hom.)
• Consequence: RAD51B NM_133510.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.19
• Publications: 16 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011664689).
• BP6: Variant 14-67887067-G-T is Benign according to our data. Variant chr14-67887067-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 584554.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.619G>T	p.Val207Leu	missense	Exon 7 of 11	NP_598194.1	O15315-2
	RAD51B	NM_001321821.2		c.619G>T	p.Val207Leu	missense	Exon 7 of 11	NP_001308750.1	C9JYJ0
	RAD51B	NM_133509.5		c.619G>T	p.Val207Leu	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.619G>T	p.Val207Leu	missense	Exon 7 of 11	ENSP00000418859.1	O15315-2
	RAD51B	ENST00000487861.5	TSL:1	c.619G>T	p.Val207Leu	missense	Exon 7 of 11	ENSP00000419881.1	C9JYJ0
	RAD51B	ENST00000487270.5	TSL:1	c.619G>T	p.Val207Leu	missense	Exon 7 of 11	ENSP00000419471.1	O15315-3

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00401

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00164 AC: 395 AN: 240472 AF XY: 0.00156

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.000210

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00290

Gnomad OTH exome AF: 0.000847

GnomAD4 exome AF: 0.00303 AC: 4277 AN: 1410806 Hom.: 8 Cov.: 30 AF XY: 0.00289 AC XY: 2030 AN XY: 703024

African (AFR) AF: 0.000907 AC: 29 AN: 31956

American (AMR) AF: 0.00151 AC: 63 AN: 41744

Ashkenazi Jewish (ASJ) AF: 0.000355 AC: 9 AN: 25344

East Asian (EAS) AF: 0.00 AC: 0 AN: 39202

South Asian (SAS) AF: 0.00 AC: 0 AN: 81056

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53106

Middle Eastern (MID) AF: 0.00177 AC: 10 AN: 5636

European-Non Finnish (NFE) AF: 0.00374 AC: 4019 AN: 1074234

Other (OTH) AF: 0.00241 AC: 141 AN: 58528

GnomAD4 genome AF: 0.00221 AC: 336 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74430

African (AFR) AF: 0.000698 AC: 29 AN: 41560

American (AMR) AF: 0.00176 AC: 27 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

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

European-Non Finnish (NFE) AF: 0.00401 AC: 273 AN: 68008

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00208 Hom.: 0

Bravo AF: 0.00251

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00137 AC: 167

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.59	N
PhyloP100		2.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.15
Sift	Benign	0.41	T
Sift4G	Benign	0.18	T
Polyphen		0.11	B
Vest4		0.38
MutPred		0.49		Gain of catalytic residue at V207 (P = 0.0019)
MVP		0.61
MPC		0.25
ClinPred		0.013	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.58
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28908168; hg19: chr14-68353784;