Genetic Variant RNF223:p.Arg181Trp (chr1-1072026-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001205252.2(RNF223):c.541C>T(p.Arg181Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000905 in 1,493,218 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00092 ( 1 hom. )

Consequence

RNF223
NM_001205252.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.806

Variant links:

Genes affected

RNF223 (HGNC:40020): (ring finger protein 223) Predicted to enable metal ion binding activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

RNF223 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025728136).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF223	NM_001205252.2 link	c.541C>T	p.Arg181Trp	missense_variant	Exon 2 of 2	ENST00000453464.3	NP_001192181.1	E7ERA6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF223	ENST00000453464.3 link	c.541C>T	p.Arg181Trp	missense_variant	Exon 2 of 2	2	NM_001205252.2	ENSP00000410533.1		E7ERA6

Frequencies

GnomAD3 genomes

AF:

0.000769

AC:

117

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000836

AC:

AN:

89674

Hom.:

AF XY:

0.000950

AC XY:

AN XY:

50548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000869

Gnomad ASJ exome

AF:

0.000157

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000128

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.00145

GnomAD4 exome

AF:

0.000921

AC:

1235

AN:

1340970

Hom.:

Cov.:

AF XY:

0.000945

AC XY:

625

AN XY:

661054

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000615

Gnomad4 ASJ exome

AF:

0.000213

Gnomad4 EAS exome

AF:

0.0000306

Gnomad4 SAS exome

AF:

0.000192

Gnomad4 FIN exome

AF:

0.0000905

Gnomad4 NFE exome

AF:

0.00108

Gnomad4 OTH exome

AF:

0.000663

GnomAD4 genome

AF:

0.000768

AC:

117

AN:

152248

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.000816

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000136

AC:

Asia WGS

AF:

0.000291

AC:

AN:

3454

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.541C>T (p.R181W) alteration is located in exon 2 (coding exon 1) of the RNF223 gene. This alteration results from a C to T substitution at nucleotide position 541, causing the arginine (R) at amino acid position 181 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0094

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.026

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.17

Sift

Benign

0.032

Sift4G

Uncertain

0.058

Vest4

0.090

MVP

0.56

ClinPred

0.046

GERP RS

1.9

Varity_R

0.051

gMVP

0.34

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