chr3-49691200-G-C

Position:

• chr3-49691200-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022064.5(RNF123):​c.35G>C​(p.Arg12Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. R12C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RNF123 NM_022064.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

Genes affected

RNF123 (HGNC:21148): (ring finger protein 123) The protein encoded by this gene contains a C-terminal RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions, and an N-terminal SPRY domain. This protein displays E3 ubiquitin ligase activity toward the cyclin-dependent kinase inhibitor 1B which is also known as p27 or KIP1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

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=0.21407378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF123	NM_022064.5	c.35G>C	p.Arg12Pro	missense_variant	2/39	ENST00000327697.11
RNF123	NR_135218.2	n.121G>C		non_coding_transcript_exon_variant	2/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF123	ENST00000327697.11	c.35G>C	p.Arg12Pro	missense_variant	2/39	1	NM_022064.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461574 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727102

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2023

The c.35G>C (p.R12P) alteration is located in exon 2 (coding exon 1) of the RNF123 gene. This alteration results from a G to C substitution at nucleotide position 35, causing the arginine (R) at amino acid position 12 to be replaced by a proline (P). 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	0.25
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;T;.
Eigen	Benign	-0.0060
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.90	N;D;.
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D;D;.
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.67	P;.;.
Vest4		0.60
MutPred		0.27		Loss of MoRF binding (P = 0.0021);Loss of MoRF binding (P = 0.0021);Loss of MoRF binding (P = 0.0021);
MVP		0.66
MPC		0.46
ClinPred		0.75	D
GERP RS		2.3
Varity_R		0.27
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs200056189; hg19: chr3-49728633;