chr12-121420302-G-A

Position:

• chr12-121420302-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025126.4(RNF34):​c.694G>A​(p.Asp232Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,432,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RNF34 NM_025126.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

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]

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]

RNF34 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.088828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF34	NM_025126.4	c.694G>A	p.Asp232Asn	missense_variant	4/6	ENST00000361234.10	NP_079402.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF34	ENST00000361234.10	c.694G>A	p.Asp232Asn	missense_variant	4/6	1	NM_025126.4	ENSP00000355137.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432280 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 710888

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Oct 28, 2024

The c.697G>A (p.D233N) alteration is located in exon 5 (coding exon 4) of the RNF34 gene. This alteration results from a G to A substitution at nucleotide position 697, causing the aspartic acid (D) at amino acid position 233 to be replaced by an asparagine (N). 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	0.083
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T;.;.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.089	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.12	N;.;N;N
REVEL	Benign	0.047
Sift	Benign	0.37	T;.;T;T
Sift4G	Benign	0.49	T;T;T;T
Polyphen		0.11	B;.;B;.
Vest4		0.37
MutPred		0.18		Loss of helix (P = 0.0167);.;.;Loss of helix (P = 0.0167);
MVP		0.34
MPC		0.47
ClinPred		0.30	T
GERP RS		3.6
Varity_R		0.033
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs964455463; hg19: chr12-121858105; COSMIC: COSV63443450; COSMIC: COSV63443450;