12-121417808-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_025126.4(RNF34):c.530G>A(p.Arg177His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,614,086 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (32 hom.)
• Consequence: RNF34 NM_025126.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.54

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017191768).
• BP6: Variant 12-121417808-G-A is Benign according to our data. Variant chr12-121417808-G-A is described in ClinVar as [Benign]. Clinvar id is 778448.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0014 (2050/1461880) while in subpopulation AMR AF= 0.0335 (1499/44724). AF 95% confidence interval is 0.0321. There are 32 homozygotes in gnomad4_exome. There are 883 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF34	NM_025126.4	c.530G>A	p.Arg177His	missense_variant	3/6	ENST00000361234.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF34	ENST00000361234.10	c.530G>A	p.Arg177His	missense_variant	3/6	1	NM_025126.4	P4

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 337 AN: 152088 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00567 AC: 1425 AN: 251420 Hom.: 29 AF XY: 0.00425 AC XY: 577 AN XY: 135874

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.0350

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00935

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00140 AC: 2050 AN: 1461880 Hom.: 32 Cov.: 32 AF XY: 0.00121 AC XY: 883 AN XY: 727240

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.0335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0101

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152206 Hom.: 5 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74392

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0129

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000920 Hom.: 1

Bravo AF: 0.00447

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00453 AC: 550

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	19
Dann	Benign	0.94
DEOGEN2	Benign	0.040	T;.;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.71	T;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.3	N;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.44	N;N;N
REVEL	Benign	0.046
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.10
MVP		0.28
MPC		0.60
ClinPred		0.0062	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.017
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41507449; hg19: chr12-121855611; COSMIC: COSV63441979; COSMIC: COSV63441979;