1-1071981-G-A

Variant names:

• chr1-1071981-G-A
• rs769166737
• NM_001205252.2:c.586C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001205252.2(RNF223):​c.586C>T​(p.Arg196Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,371,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: RNF223 NM_001205252.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33

Genes affected

RNF223 (HGNC:40020): (ring finger protein 223) 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF223	NM_001205252.2	c.586C>T	p.Arg196Cys	missense_variant	Exon 2 of 2	ENST00000453464.3	NP_001192181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF223	ENST00000453464.3	c.586C>T	p.Arg196Cys	missense_variant	Exon 2 of 2	2	NM_001205252.2	ENSP00000410533.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000153 AC: 21 AN: 1371140 Hom.: 0 Cov.: 37 AF XY: 0.0000177 AC XY: 12 AN XY: 676624

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000577

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000181

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.0000523

GnomAD4 genome Cov.: 34

ExAC AF: 0.000162 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.586C>T (p.R196C) alteration is located in exon 2 (coding exon 1) of the RNF223 gene. This alteration results from a C to T substitution at nucleotide position 586, causing the arginine (R) at amino acid position 196 to be replaced by a cysteine (C). 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	0.30
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.058	T
Vest4		0.47
MutPred		0.34		Loss of MoRF binding (P = 0.017);
MVP		0.74
ClinPred		0.79	D
GERP RS		3.3
Varity_R		0.14
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs769166737; hg19: chr1-1007361; COSMIC: COSV105343892; COSMIC: COSV105343892;