17-8393268-C-T

Variant names:

• chr17-8393268-C-T
• rs772241278
• NM_001146684.3:c.194G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.53

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]

ACMG classification

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
RNF222	NM_001146684.3	c.194G>A	p.Arg65His	missense_variant	Exon 3 of 3	ENST00000399398.3	NP_001140156.1
RNF222	XM_011523978.4	c.194G>A	p.Arg65His	missense_variant	Exon 3 of 3		XP_011522280.1
RNF222	XM_011523980.4	c.194G>A	p.Arg65His	missense_variant	Exon 2 of 2		XP_011522282.1
RNF222	XM_011523981.4	c.194G>A	p.Arg65His	missense_variant	Exon 2 of 2		XP_011522283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF222	ENST00000399398.3	c.194G>A	p.Arg65His	missense_variant	Exon 3 of 3	5	NM_001146684.3	ENSP00000382330.1
RNF222	ENST00000344001.3	c.194G>A	p.Arg65His	missense_variant	Exon 1 of 1	6		ENSP00000343799.3

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

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

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

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

Other links and lift over

dbSNP: rs772241278; hg19: chr17-8296586;