Variant 6-125076745-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001286398.3(RNF217):c.1370G>A(p.Arg457His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,613,338 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

Frequency

Genomes: 𝑓 0.0054 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 25 hom. )

Consequence

RNF217
NM_001286398.3 missense

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 7.69

Variant links:

Genes affected

RNF217 (HGNC:21487): (ring finger protein 217) This protein encoded by this gene is a member of the RING1-IBR-RING24 (RBR) ubiquitin protein ligase family, and it belongs to a subfamily of these proteins that contain a transmembrane domain. This protein can interact with the HAX1 anti-apoptotic protein via its C-terminal RING finger motif, which suggests a role in apoptosis signaling. It is thought that deregulation of this gene can be a mechanism in leukemogenesis. Mutations in the region encoding the protein GXXXG motif, which appears to be necessary for protein self-association, have been found in human cancers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2016]

RNF217 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008839369).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00319 (4660/1461200) while in subpopulation MID AF= 0.0231 (133/5758). AF 95% confidence interval is 0.0199. There are 25 homozygotes in gnomad4_exome. There are 2386 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF217	NM_001286398.3 linkuse as main transcript	c.1370G>A	p.Arg457His	missense_variant	4/6	ENST00000521654.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF217	ENST00000521654.7 linkuse as main transcript	c.1370G>A	p.Arg457His	missense_variant	4/6	2	NM_001286398.3	P1	Q8TC41-1

Frequencies

GnomAD3 genomes

AF:

0.00541

AC:

823

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00889

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00872

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00395

Gnomad FIN

AF:

0.000850

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00315

Gnomad OTH

AF:

0.00960

GnomAD3 exomes

AF:

0.00439

AC:

1102

AN:

251090

Hom.:

AF XY:

0.00449

AC XY:

609

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.00886

Gnomad AMR exome

AF:

0.00519

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00441

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00382

Gnomad OTH exome

AF:

0.00800

GnomAD4 exome

AF:

0.00319

AC:

4660

AN:

1461200

Hom.:

Cov.:

AF XY:

0.00328

AC XY:

2386

AN XY:

726902

show subpopulations

Gnomad4 AFR exome

AF:

0.00906

Gnomad4 AMR exome

AF:

0.00513

Gnomad4 ASJ exome

AF:

0.0145

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00470

Gnomad4 FIN exome

AF:

0.000655

Gnomad4 NFE exome

AF:

0.00256

Gnomad4 OTH exome

AF:

0.00535

GnomAD4 genome

AF:

0.00541

AC:

823

AN:

152138

Hom.:

Cov.:

AF XY:

0.00546

AC XY:

406

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00886

Gnomad4 AMR

AF:

0.00870

Gnomad4 ASJ

AF:

0.0150

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00395

Gnomad4 FIN

AF:

0.000850

Gnomad4 NFE

AF:

0.00315

Gnomad4 OTH

AF:

0.00950

Alfa

AF:

0.00411

Hom.:

Bravo

AF:

0.00593

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00443

AC:

538

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00578

EpiControl

AF:

0.00510

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Multiple sclerosis, susceptibility to

Other:1

risk factor, no assertion criteria provided

research

Department of Molecular Bıology and Genetics, Istanbul Technical University

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D;D;D

MetaRNN

Benign

0.0088

T;T;T;T

MetaSVM

Benign

-0.87

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.79

Sift4G

Benign

0.090

T;D;T;T

Vest4

0.48

MVP

0.78

MPC

0.59

ClinPred

0.039

GERP RS

4.7

Varity_R

0.26

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over