rs533469408

Variant names:

• chr1-19814578-G-A
• rs533469408
• NM_019062.2:c.524C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-19814578-G-A
• chr1-19814578-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_019062.2(RNF186):​c.524C>T​(p.Pro175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,614,160 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: RNF186 NM_019062.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16
• Publications: 1 publications found

Genes affected

RNF186 (HGNC:25978): (ring finger protein 186) Enables ubiquitin-protein transferase activity. Involved in several processes, including intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; proteasome-mediated ubiquitin-dependent protein catabolic process; and protein ubiquitination. Located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

RNF186-AS1 (HGNC:41127): (RNF186 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09225136).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF186	NM_019062.2	c.524C>T	p.Pro175Leu	missense_variant	Exon 1 of 1	ENST00000375121.4	NP_061935.1
RNF186-AS1	NR_186008.1	n.145+25G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF186	ENST00000375121.4	c.524C>T	p.Pro175Leu	missense_variant	Exon 1 of 1	6	NM_019062.2	ENSP00000364263.2
RNF186-AS1	ENST00000454736.2	n.200+25G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000207 AC: 52 AN: 251440 AF XY: 0.000258

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000161 AC: 236 AN: 1461890 Hom.: 1 Cov.: 30 AF XY: 0.000199 AC XY: 145 AN XY: 727248

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000904 AC: 78 AN: 86256

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000114 AC: 127 AN: 1112012

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74458

African (AFR) AF: 0.000289 AC: 12 AN: 41564

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.524C>T (p.P175L) alteration is located in exon 1 (coding exon 1) of the RNF186 gene. This alteration results from a C to T substitution at nucleotide position 524, causing the proline (P) at amino acid position 175 to be replaced by a leucine (L). 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	0.20
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.2
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.33
MVP		0.66
MPC		0.66
ClinPred		0.18	T
GERP RS		4.8
Varity_R		0.27
gMVP		0.50
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs533469408; hg19: chr1-20141071;