12-121420313-A-T

Variant names:

• chr12-121420313-A-T
• rs61751317
• NM_025126.4:c.705A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_025126.4(RNF34):​c.705A>T​(p.Glu235Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,576,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: RNF34 NM_025126.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.83
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012243032).
• BP6: Variant 12-121420313-A-T is Benign according to our data. Variant chr12-121420313-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2377433.Status of the report is criteria_provided_single_submitter, 1 stars.

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.705A>T	p.Glu235Asp	missense	Exon 4 of 6	NP_079402.2
	RNF34	NM_001394208.1		c.708A>T	p.Glu236Asp	missense	Exon 6 of 8	NP_001381137.1	Q969K3-2
	RNF34	NM_194271.3		c.708A>T	p.Glu236Asp	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.705A>T	p.Glu235Asp	missense	Exon 4 of 6	ENSP00000355137.5	Q969K3-1
	RNF34	ENST00000392464.3	TSL:5	c.705A>T	p.Glu235Asp	missense	Exon 4 of 7	ENSP00000376257.2	H7BYJ1
	RNF34	ENST00000392465.7	TSL:5	c.708A>T	p.Glu236Asp	missense	Exon 5 of 7	ENSP00000376258.3	Q969K3-2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000153 AC: 29 AN: 189378 AF XY: 0.000216

Gnomad AFR exome AF: 0.0000861

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000110

Gnomad NFE exome AF: 0.000254

Gnomad OTH exome AF: 0.000393

GnomAD4 exome AF: 0.000173 AC: 246 AN: 1424586 Hom.: 0 Cov.: 29 AF XY: 0.000174 AC XY: 123 AN XY: 706238

African (AFR) AF: 0.0000312 AC: 1 AN: 32058

American (AMR) AF: 0.00 AC: 0 AN: 39336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25570

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 37042

South Asian (SAS) AF: 0.000146 AC: 12 AN: 82052

European-Finnish (FIN) AF: 0.000155 AC: 8 AN: 51596

Middle Eastern (MID) AF: 0.000524 AC: 3 AN: 5722

European-Non Finnish (NFE) AF: 0.000198 AC: 216 AN: 1092112

Other (OTH) AF: 0.0000846 AC: 5 AN: 59098

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74364

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000284 Hom.: 0

Bravo AF: 0.000178

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000184 AC: 22

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.057
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.0010
DANN	Benign	0.34
DEOGEN2	Benign	0.050	T
Eigen	Benign	-3.2
Eigen_PC	Benign	-3.2
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.86	L
PhyloP100		-3.8
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.032
Sift	Benign	0.58	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.19		Loss of helix (P = 0.079)
MVP		0.18
MPC		0.44
ClinPred		0.017	T
GERP RS		-9.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.041
gMVP		0.25
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs61751317; hg19: chr12-121858116; COSMIC: COSV100772183; COSMIC: COSV100772183;