19-49011025-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_006666.3(RUVBL2):c.814G>A(p.Val272Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUVBL2 NM_006666.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.00

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RUVBL2
• BP4: Computational evidence support a benign effect (MetaRNN=0.2847619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUVBL2	NM_006666.3	c.814G>A	p.Val272Ile	missense_variant	10/15	ENST00000595090.6
RUVBL2	NM_001321190.2	c.712G>A	p.Val238Ile	missense_variant	10/15
RUVBL2	NM_001321191.1	c.679G>A	p.Val227Ile	missense_variant	10/15
RUVBL2	NR_135578.2	n.828G>A		non_coding_transcript_exon_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUVBL2	ENST00000595090.6	c.814G>A	p.Val272Ile	missense_variant	10/15	1	NM_006666.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The c.814G>A (p.V272I) alteration is located in exon 10 (coding exon 10) of the RUVBL2 gene. This alteration results from a G to A substitution at nucleotide position 814, causing the valine (V) at amino acid position 272 to be replaced by an isoleucine (I). 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	Benign	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	23
Dann	Benign	0.97
DEOGEN2	Benign	0.25	T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.24
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;.;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.036	B;.;.
Vest4		0.33
MutPred		0.39		Gain of helix (P = 0.062);.;.;
MVP		0.33
MPC		0.82
ClinPred		0.83	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49514282;