dbSNP rs556658999: RNF222:p.Arg76Leu (chr17-8393235-C-A) – 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.227G>T(p.Arg76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

RNF222
NM_001146684.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.357

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:

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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=0.07571325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF222	NM_001146684.3 link	c.227G>T	p.Arg76Leu	missense_variant	Exon 3 of 3	ENST00000399398.3	NP_001140156.1	A6NCQ9
RNF222	XM_011523978.4 link	c.227G>T	p.Arg76Leu	missense_variant	Exon 3 of 3		XP_011522280.1	A6NCQ9
RNF222	XM_011523980.4 link	c.227G>T	p.Arg76Leu	missense_variant	Exon 2 of 2		XP_011522282.1	A6NCQ9
RNF222	XM_011523981.4 link	c.227G>T	p.Arg76Leu	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.227G>T	p.Arg76Leu	missense_variant	Exon 3 of 3	5	NM_001146684.3	ENSP00000382330.1		A6NCQ9
RNF222	ENST00000344001.3 link	c.227G>T	p.Arg76Leu	missense_variant	Exon 1 of 1	6		ENSP00000343799.3		A6NCQ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000656

AC:

AN:

152394

Hom.:

AF XY:

0.0000123

AC XY:

AN XY:

81286

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000439

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398716

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689886

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000385

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.00077

T;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.0075

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.64

T;.

M_CAP

Benign

0.0055

MetaRNN

Benign

0.076

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.50

N;N

REVEL

Benign

0.079

Sift

Benign

0.35

T;T

Sift4G

Benign

0.78

T;T

Polyphen

0.013

B;B

Vest4

0.12

MutPred

0.47

Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);

MVP

0.095

ClinPred

0.93

GERP RS

4.4

Varity_R

0.17

gMVP

0.36

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over