17-8393131-C-T

Variant names:

• chr17-8393131-C-T
• rs1329313606
• NM_001146684.3:c.331G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001146684.3(RNF222):​c.331G>A​(p.Ala111Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,383,402 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RNF222 NM_001146684.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.405

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 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=0.030542076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF222	NM_001146684.3	c.331G>A	p.Ala111Thr	missense_variant	Exon 3 of 3	ENST00000399398.3	NP_001140156.1
RNF222	XM_011523978.4	c.331G>A	p.Ala111Thr	missense_variant	Exon 3 of 3		XP_011522280.1
RNF222	XM_011523980.4	c.331G>A	p.Ala111Thr	missense_variant	Exon 2 of 2		XP_011522282.1
RNF222	XM_011523981.4	c.331G>A	p.Ala111Thr	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.331G>A	p.Ala111Thr	missense_variant	Exon 3 of 3	5	NM_001146684.3	ENSP00000382330.1
RNF222	ENST00000344001.3	c.331G>A	p.Ala111Thr	missense_variant	Exon 1 of 1	6		ENSP00000343799.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000148 AC: 2 AN: 134910 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 72448

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000408

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 14 AN: 1383402 Hom.: 0 Cov.: 34 AF XY: 0.0000132 AC XY: 9 AN XY: 681074

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: 0.0000257

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000112

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000368 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.331G>A (p.A111T) 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 331, causing the alanine (A) at amino acid position 111 to be replaced by a threonine (T). 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	0.071
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.91
DANN	Benign	0.84
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.38	T;.
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.031	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.14	N;N
REVEL	Benign	0.0040
Sift	Benign	0.13	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.014	B;B
Vest4		0.016
MutPred		0.17		Gain of glycosylation at A111 (P = 0.0018);Gain of glycosylation at A111 (P = 0.0018);
MVP		0.014
ClinPred		0.076	T
GERP RS		-1.4
Varity_R		0.042
gMVP		0.27

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: rs1329313606; hg19: chr17-8296449;