1-19814633-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_019062.2(RNF186):​c.469G>A​(p.Ala157Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A157V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

RNF186
NM_019062.2 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.79

Publications

2 publications found
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009694815).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RNF186NM_019062.2 linkc.469G>A p.Ala157Thr missense_variant Exon 1 of 1 ENST00000375121.4 NP_061935.1 Q9NXI6
RNF186-AS1NR_186008.1 linkn.145+80C>T intron_variant Intron 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RNF186ENST00000375121.4 linkc.469G>A p.Ala157Thr missense_variant Exon 1 of 1 6 NM_019062.2 ENSP00000364263.2 Q9NXI6
RNF186-AS1ENST00000454736.2 linkn.200+80C>T intron_variant Intron 1 of 1 2

Frequencies

GnomAD3 genomes
AF:
0.000263
AC:
40
AN:
152138
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000785
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000772
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000434
AC:
109
AN:
251422
AF XY:
0.000346
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00211
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000272
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000202
Gnomad OTH exome
AF:
0.000815
GnomAD4 exome
AF:
0.000222
AC:
325
AN:
1461892
Hom.:
0
Cov.:
30
AF XY:
0.000223
AC XY:
162
AN XY:
727246
show subpopulations
African (AFR)
AF:
0.0000896
AC:
3
AN:
33480
American (AMR)
AF:
0.00190
AC:
85
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.000126
AC:
5
AN:
39700
South Asian (SAS)
AF:
0.0000348
AC:
3
AN:
86258
European-Finnish (FIN)
AF:
0.0000749
AC:
4
AN:
53420
Middle Eastern (MID)
AF:
0.00104
AC:
6
AN:
5768
European-Non Finnish (NFE)
AF:
0.000189
AC:
210
AN:
1112010
Other (OTH)
AF:
0.000149
AC:
9
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
21
41
62
82
103
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000263
AC:
40
AN:
152256
Hom.:
0
Cov.:
33
AF XY:
0.000255
AC XY:
19
AN XY:
74444
show subpopulations
African (AFR)
AF:
0.0000481
AC:
2
AN:
41560
American (AMR)
AF:
0.000784
AC:
12
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.000773
AC:
4
AN:
5172
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.000294
AC:
20
AN:
68002
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000304
Hom.:
1
Bravo
AF:
0.000230
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000338
AC:
41
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000382
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 28, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.469G>A (p.A157T) alteration is located in exon 1 (coding exon 1) of the RNF186 gene. This alteration results from a G to A substitution at nucleotide position 469, causing the alanine (A) at amino acid position 157 to be replaced by a threonine (T). 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
0.10
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.011
T
Eigen
Benign
0.098
Eigen_PC
Benign
0.085
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.54
T
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.0097
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
M
PhyloP100
1.8
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.88
N
REVEL
Benign
0.068
Sift
Benign
0.14
T
Sift4G
Benign
0.22
T
Polyphen
0.94
P
Vest4
0.16
MVP
0.33
MPC
0.42
ClinPred
0.022
T
GERP RS
4.7
Varity_R
0.065
gMVP
0.23
Mutation Taster
=97/3
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

Publications

Other links and lift over

dbSNP: rs41264109; hg19: chr1-20141126; COSMIC: COSV64296711; API