Variant chr12-121416174-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025126.4(RNF34):c.22A>G(p.Met8Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RNF34
NM_025126.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.25

Variant links:

Genes affected

RNF34 (HGNC:17297): (ring finger protein 34) The protein encoded by this gene contains a RINF finger, a motif known to be involved in protein-protein and protein-DNA interactions. This protein interacts with DNAJA3/hTid-1, which is a DnaJ protein reported to function as a modulator of apoptosis. Overexpression of this gene in Hela cells was shown to confer the resistance to TNF-alpha induced apoptosis, suggesting an anti-apoptotic function of this protein. This protein can be cleaved by caspase-3 during the induction of apoptosis. This protein also targets p53 and phospho-p53 for degradation. Alternatively splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2012]

RNF34 links:

KDM2B (HGNC:13610): (lysine demethylase 2B) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class. Multiple alternatively spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]

KDM2B links:

RNF34 (HGNC:):

RNF34 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF34	NM_025126.4 linkuse as main transcript	c.22A>G	p.Met8Val	missense_variant	2/6	ENST00000361234.10	NP_079402.2	Q969K3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF34	ENST00000361234.10 linkuse as main transcript	c.22A>G	p.Met8Val	missense_variant	2/6	1	NM_025126.4	ENSP00000355137.5		Q969K3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251444

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.25A>G (p.M9V) alteration is located in exon 3 (coding exon 2) of the RNF34 gene. This alteration results from a A to G substitution at nucleotide position 25, causing the methionine (M) at amino acid position 9 to be replaced by a valine (V). 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

0.13

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

T;.;T;T;T;.

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.66

D;D;D;D;D;D

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.7

L;.;.;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.7

N;N;N;N;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

D;D;D;D;D;.

Sift4G

Uncertain

0.0080

D;D;D;D;D;D

Polyphen

0.79

P;P;P;.;.;.

Vest4

0.83

MutPred

0.53

Gain of catalytic residue at S7 (P = 6e-04);.;.;Gain of catalytic residue at S7 (P = 6e-04);.;.;

MVP

0.78

MPC

0.52

ClinPred

0.60

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.81

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

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