chr12-121420302-G-A

Variant names:

• chr12-121420302-G-A
• rs964455463
• NM_025126.4:c.694G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/22 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)
  • 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
• Publications: 1 publications found

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]

KDM2B Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025126.4. 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
	RNF34	NM_025126.4	MANE Select	c.694G>A	p.Asp232Asn	missense	Exon 4 of 6	NP_079402.2
	RNF34	NM_001394208.1		c.697G>A	p.Asp233Asn	missense	Exon 6 of 8	NP_001381137.1	Q969K3-2
	RNF34	NM_194271.3		c.697G>A	p.Asp233Asn	missense	Exon 5 of 7	NP_919247.1	Q969K3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF34	ENST00000361234.10	TSL:1 MANE Select	c.694G>A	p.Asp232Asn	missense	Exon 4 of 6	ENSP00000355137.5	Q969K3-1
	RNF34	ENST00000392464.3	TSL:5	c.694G>A	p.Asp232Asn	missense	Exon 4 of 7	ENSP00000376257.2	H7BYJ1
	RNF34	ENST00000392465.7	TSL:5	c.697G>A	p.Asp233Asn	missense	Exon 5 of 7	ENSP00000376258.3	Q969K3-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 199882 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 32322

American (AMR) AF: 0.00 AC: 0 AN: 40870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25710

East Asian (EAS) AF: 0.00 AC: 0 AN: 37676

South Asian (SAS) AF: 0.00 AC: 0 AN: 82826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1095720

Other (OTH) AF: 0.00 AC: 0 AN: 59322

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N
PhyloP100		2.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.047
Sift	Benign	0.37	T
Sift4G	Benign	0.49	T
Polyphen		0.11	B
Vest4		0.37
MutPred		0.18		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
Mutation Taster		=86/14	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: rs964455463; hg19: chr12-121858105; COSMIC: COSV63443450; COSMIC: COSV63443450;