Genetic Variant RNF223:p.Pro234Leu (chr1-1071866-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.701C>T(p.Pro234Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000473 in 1,522,758 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000045 ( 1 hom. )

Consequence

RNF223
NM_001205252.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.06

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=0.05876535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF223	NM_001205252.2 link	c.701C>T	p.Pro234Leu	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.701C>T	p.Pro234Leu	missense_variant	Exon 2 of 2	2	NM_001205252.2	ENSP00000410533.1		E7ERA6

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000820

AC:

AN:

121942

Hom.:

AF XY:

0.0000448

AC XY:

AN XY:

66916

show subpopulations

Gnomad AFR exome

AF:

0.000177

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.000642

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000467

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000222

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1370440

Hom.:

Cov.:

AF XY:

0.0000429

AC XY:

AN XY:

676126

show subpopulations

Gnomad4 AFR exome

AF:

0.000130

Gnomad4 AMR exome

AF:

0.0000869

Gnomad4 ASJ exome

AF:

0.000606

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000640

Gnomad4 FIN exome

AF:

0.0000301

Gnomad4 NFE exome

AF:

0.0000168

Gnomad4 OTH exome

AF:

0.000245

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000869

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.701C>T (p.P234L) 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 701, causing the proline (P) at amino acid position 234 to be replaced by a leucine (L). 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

0.075

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0068

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.28

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.059

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.34

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.57

REVEL

Benign

0.18

Sift

Benign

0.29

Sift4G

Benign

0.33

Vest4

0.074

MutPred

0.20

Loss of glycosylation at P234 (P = 0.003);

MVP

0.65

ClinPred

0.032

GERP RS

2.1

Varity_R

0.036

gMVP

0.23

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