rs34823813

Variant names:

• chr3-49712543-G-A
• rs34823813
• NM_022064.5:c.2561G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022064.5(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. 14/21 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 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 NM_022064.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65
• Publications: 31 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022064.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF123	NM_022064.5	MANE Select	c.2561G>A	p.Arg854His	missense	Exon 27 of 39	NP_071347.2
	RNF123	NR_135218.2		n.2651G>A		non_coding_transcript_exon	Exon 27 of 39

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF123	ENST00000327697.11	TSL:1 MANE Select	c.2561G>A	p.Arg854His	missense	Exon 27 of 39	ENSP00000328287.6
	RNF123	ENST00000432042.5	TSL:1	c.2123G>A	p.Arg708His	missense	Exon 24 of 24	ENSP00000392443.1
	RNF123	ENST00000457726.5	TSL:1	n.*399G>A		non_coding_transcript_exon	Exon 27 of 39	ENSP00000394369.1

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

GnomAD2 exomes AF: 0.0775 AC: 19485 AN: 251388 AF XY: 0.0785

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 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

African (AFR) AF: 0.0145 AC: 485 AN: 33480

American (AMR) AF: 0.0485 AC: 2167 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 3529 AN: 26134

East Asian (EAS) AF: 0.0201 AC: 799 AN: 39700

South Asian (SAS) AF: 0.0541 AC: 4665 AN: 86256

European-Finnish (FIN) AF: 0.0960 AC: 5123 AN: 53376

Middle Eastern (MID) AF: 0.0694 AC: 400 AN: 5766

European-Non Finnish (NFE) AF: 0.102 AC: 113058 AN: 1111998

Other (OTH) AF: 0.0860 AC: 5196 AN: 60396

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

African (AFR) AF: 0.0180 AC: 750 AN: 41568

American (AMR) AF: 0.0632 AC: 967 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 493 AN: 3472

East Asian (EAS) AF: 0.0255 AC: 132 AN: 5178

South Asian (SAS) AF: 0.0564 AC: 272 AN: 4826

European-Finnish (FIN) AF: 0.0957 AC: 1016 AN: 10614

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0985 AC: 6701 AN: 68014

Other (OTH) AF: 0.0744 AC: 157 AN: 2110

Alfa AF: 0.0892 Hom.: 1449

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 v4.9

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
Eigen	Benign	0.078
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.22
Sift	Benign	0.097	T
Sift4G	Benign	0.30	T
Polyphen		0.99	D
Vest4		0.18
MPC		0.32
ClinPred		0.018	T
GERP RS		5.0
PromoterAI		0.033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.26
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34823813; hg19: chr3-49749976; COSMIC: COSV57539218; COSMIC: COSV57539218;