12-121420313-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 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. 15/21 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

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:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 2377433.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF34	NM_025126.4	c.705A>T	p.Glu235Asp	missense_variant	4/6	ENST00000361234.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF34	ENST00000361234.10	c.705A>T	p.Glu235Asp	missense_variant	4/6	1	NM_025126.4	P4

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

GnomAD3 exomes AF: 0.000153 AC: 29 AN: 189378 Hom.: 0 AF XY: 0.000216 AC XY: 22 AN XY: 101692

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 SAS exome AF: 0.000157

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

Gnomad4 AFR exome AF: 0.0000312

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000270

Gnomad4 SAS exome AF: 0.000146

Gnomad4 FIN exome AF: 0.000155

Gnomad4 NFE exome AF: 0.000198

Gnomad4 OTH exome AF: 0.0000846

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

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

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;.;.;T
Eigen	Benign	-3.2
Eigen_PC	Benign	-3.2
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.44	T;T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.86	L;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.23	N;.;N;N
REVEL	Benign	0.032
Sift	Benign	0.58	T;.;T;T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.11
MutPred		0.19		Loss of helix (P = 0.079);.;.;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

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

LitVar

Other links and lift over

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