17-8393268-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001146684.3(RNF222):​c.194G>A​(p.Arg65His) variant causes a missense change. The variant allele was found at a frequency of 0.00000429 in 1,399,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R65C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

RNF222
NM_001146684.3 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.53
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RNF222NM_001146684.3 linkc.194G>A p.Arg65His missense_variant Exon 3 of 3 ENST00000399398.3 NP_001140156.1 A6NCQ9
RNF222XM_011523978.4 linkc.194G>A p.Arg65His missense_variant Exon 3 of 3 XP_011522280.1 A6NCQ9
RNF222XM_011523980.4 linkc.194G>A p.Arg65His missense_variant Exon 2 of 2 XP_011522282.1 A6NCQ9
RNF222XM_011523981.4 linkc.194G>A p.Arg65His missense_variant Exon 2 of 2 XP_011522283.1 A6NCQ9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RNF222ENST00000399398.3 linkc.194G>A p.Arg65His missense_variant Exon 3 of 3 5 NM_001146684.3 ENSP00000382330.1 A6NCQ9
RNF222ENST00000344001.3 linkc.194G>A p.Arg65His missense_variant Exon 1 of 1 6 ENSP00000343799.3 A6NCQ9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000650
AC:
1
AN:
153924
Hom.:
0
AF XY:
0.0000122
AC XY:
1
AN XY:
81834
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:
0.00000429
AC:
6
AN:
1399024
Hom.:
0
Cov.:
34
AF XY:
0.00000435
AC XY:
3
AN XY:
690032
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000280
Gnomad4 SAS exome
AF:
0.0000126
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000371
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 02, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.194G>A (p.R65H) 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 194, causing the arginine (R) at amino acid position 65 to be replaced by a histidine (H). 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
Pathogenic
0.93
BayesDel_addAF
Uncertain
0.084
D
BayesDel_noAF
Uncertain
0.010
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.30
T;T
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.86
D;.
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.92
D;D
MetaSVM
Uncertain
-0.10
T
MutationAssessor
Uncertain
2.4
M;M
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-3.9
D;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.0030
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.91
MutPred
0.76
Loss of MoRF binding (P = 0.0095);Loss of MoRF binding (P = 0.0095);
MVP
0.29
ClinPred
0.99
D
GERP RS
4.4
Varity_R
0.54
gMVP
0.75

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.

Other links and lift over

dbSNP: rs772241278; hg19: chr17-8296586; API