rs34823813

Positions:

• chr3-49712543-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000327697.11(RNF123):​c.2561G>A​(p.Arg854His) variant causes a missense change. The variant allele was found at a frequency of 0.0905 in 1,614,116 control chromosomes in the GnomAD database, including 7,270 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R854G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.070 (509 hom., cov: 33)
  • Exomes 𝑓: 0.093 (6761 hom.)
• Consequence: RNF123 ENST00000327697.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002419144).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF123	NM_022064.5	c.2561G>A	p.Arg854His	missense_variant	27/39	ENST00000327697.11	NP_071347.2
RNF123	NR_135218.2	n.2651G>A		non_coding_transcript_exon_variant	27/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF123	ENST00000327697.11	c.2561G>A	p.Arg854His	missense_variant	27/39	1	NM_022064.5	ENSP00000328287	P1

Frequencies

GnomAD3 genomes AF: 0.0697 AC: 10603 AN: 152170 Hom.: 509 Cov.: 33

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0632

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.0254

Gnomad SAS AF: 0.0561

Gnomad FIN AF: 0.0957

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0985

Gnomad OTH AF: 0.0757

GnomAD3 exomes AF: 0.0775 AC: 19485 AN: 251388 Hom.: 895 AF XY: 0.0785 AC XY: 10665 AN XY: 135882

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.0466

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.0266

Gnomad SAS exome AF: 0.0530

Gnomad FIN exome AF: 0.0972

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0846

GnomAD4 exome AF: 0.0926 AC: 135422 AN: 1461828 Hom.: 6761 Cov.: 33 AF XY: 0.0915 AC XY: 66528 AN XY: 727208

Gnomad4 AFR exome AF: 0.0145

Gnomad4 AMR exome AF: 0.0485

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.0201

Gnomad4 SAS exome AF: 0.0541

Gnomad4 FIN exome AF: 0.0960

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.0860

GnomAD4 genome AF: 0.0696 AC: 10603 AN: 152288 Hom.: 509 Cov.: 33 AF XY: 0.0693 AC XY: 5162 AN XY: 74462

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.0632

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.0255

Gnomad4 SAS AF: 0.0564

Gnomad4 FIN AF: 0.0957

Gnomad4 NFE AF: 0.0985

Gnomad4 OTH AF: 0.0744

Alfa AF: 0.0936 Hom.: 1176

Bravo AF: 0.0654

TwinsUK AF: 0.109 AC: 404

ALSPAC AF: 0.101 AC: 390

ESP6500AA AF: 0.0209 AC: 92

ESP6500EA AF: 0.102 AC: 880

ExAC AF: 0.0764 AC: 9273

Asia WGS AF: 0.0310 AC: 111 AN: 3478

EpiCase AF: 0.105

EpiControl AF: 0.106

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.014	T;T
Eigen	Benign	0.078
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.053	P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.22
Sift	Benign	0.097	T;T
Sift4G	Benign	0.30	T;D
Polyphen		0.99	D;D
Vest4		0.18
MPC		0.32
ClinPred		0.018	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs34823813; hg19: chr3-49749976; COSMIC: COSV57539218; COSMIC: COSV57539218;