Genetic Variant RNF222:p.Val67Ile (chr17-8393263-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001146684.3(RNF222):c.199G>A(p.Val67Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000185 in 1,551,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

RNF222
NM_001146684.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.79

Variant links:

Genes affected

RNF222 (HGNC:34517): (ring finger protein 222) Predicted to enable metal ion binding activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

RNF222 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2376698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF222	NM_001146684.3 link	c.199G>A	p.Val67Ile	missense_variant	Exon 3 of 3	ENST00000399398.3	NP_001140156.1	A6NCQ9
RNF222	XM_011523978.4 link	c.199G>A	p.Val67Ile	missense_variant	Exon 3 of 3		XP_011522280.1	A6NCQ9
RNF222	XM_011523980.4 link	c.199G>A	p.Val67Ile	missense_variant	Exon 2 of 2		XP_011522282.1	A6NCQ9
RNF222	XM_011523981.4 link	c.199G>A	p.Val67Ile	missense_variant	Exon 2 of 2		XP_011522283.1	A6NCQ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF222	ENST00000399398.3 link	c.199G>A	p.Val67Ile	missense_variant	Exon 3 of 3	5	NM_001146684.3	ENSP00000382330.1		A6NCQ9
RNF222	ENST00000344001.3 link	c.199G>A	p.Val67Ile	missense_variant	Exon 1 of 1	6		ENSP00000343799.3		A6NCQ9

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000780

AC:

AN:

153766

Hom.:

AF XY:

0.0000978

AC XY:

AN XY:

81772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000920

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000194

AC:

271

AN:

1399010

Hom.:

Cov.:

AF XY:

0.000196

AC XY:

135

AN XY:

690036

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000840

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000231

Gnomad4 OTH exome

AF:

0.000293

GnomAD4 genome

AF:

0.000105

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199G>A (p.V67I) alteration is located in exon 3 (coding exon 1) of the RNF222 gene. This alteration results from a G to A substitution at nucleotide position 199, causing the valine (V) at amino acid position 67 to be replaced by an isoleucine (I). 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

0.22

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0084

T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.72

T;.

M_CAP

Benign

0.050

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.36

N;N

REVEL

Benign

0.19

Sift

Benign

0.045

D;D

Sift4G

Benign

0.065

T;T

Polyphen

0.99

D;D

Vest4

0.29

MVP

0.19

ClinPred

0.58

GERP RS

4.4

Varity_R

0.10

gMVP

0.17

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