Genetic Variant RUVBL2:p.Val225Met (chr19-49010497-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_006666.3(RUVBL2):c.673G>A(p.Val225Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000648 in 693,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

RUVBL2
NM_006666.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.05

Variant links:

Genes affected

RUVBL2 (HGNC:10475): (RuvB like AAA ATPase 2) This gene encodes the second human homologue of the bacterial RuvB gene. Bacterial RuvB protein is a DNA helicase essential for homologous recombination and DNA double-strand break repair. Functional analysis showed that this gene product has both ATPase and DNA helicase activities. This gene is physically linked to the CGB/LHB gene cluster on chromosome 19q13.3, and is very close (55 nt) to the LHB gene, in the opposite orientation. [provided by RefSeq, Jul 2008]

RUVBL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

BS2

High AC in GnomAdExome4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUVBL2	NM_006666.3 link	c.673G>A	p.Val225Met	missense_variant	Exon 9 of 15	ENST00000595090.6	NP_006657.1	Q9Y230-1
RUVBL2	NM_001321190.2 link	c.571G>A	p.Val191Met	missense_variant	Exon 9 of 15		NP_001308119.1	B3KNL2
RUVBL2	NM_001321191.1 link	c.538G>A	p.Val180Met	missense_variant	Exon 9 of 15		NP_001308120.1	Q9Y230-2
RUVBL2	NR_135578.2 link	n.687G>A		non_coding_transcript_exon_variant	Exon 9 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUVBL2	ENST00000595090.6 link	c.673G>A	p.Val225Met	missense_variant	Exon 9 of 15	1	NM_006666.3	ENSP00000473172.1		Q9Y230-1

Frequencies

GnomAD3 genomes

AF:

0.0000364

AC:

AN:

109964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000359

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000301

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000170

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000563

AC:

AN:

248614

Hom.:

AF XY:

0.0000815

AC XY:

AN XY:

134952

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000532

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000702

AC:

AN:

583950

Hom.:

Cov.:

AF XY:

0.0000878

AC XY:

AN XY:

307662

show subpopulations

Gnomad4 AFR exome

AF:

0.0000685

Gnomad4 AMR exome

AF:

0.0000271

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000485

Gnomad4 OTH exome

AF:

0.000126

GnomAD4 genome

AF:

0.0000364

AC:

AN:

109964

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

50070

show subpopulations

Gnomad4 AFR

AF:

0.0000359

Gnomad4 AMR

AF:

0.000138

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000301

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000170

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000744

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.673G>A (p.V225M) alteration is located in exon 9 (coding exon 9) of the RUVBL2 gene. This alteration results from a G to A substitution at nucleotide position 673, causing the valine (V) at amino acid position 225 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;T;T

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;.;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.2

M;.;.

PrimateAI

Pathogenic

0.88

Sift4G

Uncertain

0.011

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.81

MVP

0.76

MPC

1.5

ClinPred

0.95

GERP RS

4.9

Varity_R

0.79

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over