Variant 6-127287083-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001242850.2(RNF146):c.470G>T(p.Arg157Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,613,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

RNF146
NM_001242850.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.68

Variant links:

Genes affected

RNF146 (HGNC:21336): (ring finger protein 146) Enables poly-ADP-D-ribose binding activity and ubiquitin-protein transferase activity. Involved in positive regulation of canonical Wnt signaling pathway; protein ubiquitination; and ubiquitin-dependent protein catabolic process. Located in cytosol; nucleoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

RNF146 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF146	NM_001242850.2 linkuse as main transcript	c.470G>T	p.Arg157Ile	missense_variant	3/3	ENST00000368314.6	NP_001229779.1	Q9NTX7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RNF146	ENST00000368314.6 linkuse as main transcript	c.470G>T	p.Arg157Ile	missense_variant	3/3	2	NM_001242850.2	ENSP00000357297.1	Q9NTX7-1
RNF146	ENST00000610153.1 linkuse as main transcript	c.470G>T	p.Arg157Ile	missense_variant	3/3	2		ENSP00000476814.1	Q9NTX7-1
RNF146	ENST00000608991.5 linkuse as main transcript	c.467G>T	p.Arg156Ile	missense_variant	5/5	4		ENSP00000477168.1	Q9NTX7-2
RNF146	ENST00000356799.6 linkuse as main transcript	c.*475G>T		3_prime_UTR_variant	4/4	2		ENSP00000349253.3	V9GYY4

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000800

AC:

AN:

249958

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135100

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000160

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000114

AC:

166

AN:

1461204

Hom.:

Cov.:

AF XY:

0.0000977

AC XY:

AN XY:

726930

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000143

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000592

AC:

AN:

151966

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000922

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000546

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2024

The c.470G>T (p.R157I) alteration is located in exon 3 (coding exon 2) of the RNF146 gene. This alteration results from a G to T substitution at nucleotide position 470, causing the arginine (R) at amino acid position 157 to be replaced by an isoleucine (I). 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

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T;.;T;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;D;.;.

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.80

D;D;D;D;D

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.4

M;M;.;M;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.5

D;.;D;.;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

D;.;D;.;.

Sift4G

Uncertain

0.0030

.;.;D;.;D

Polyphen

1.0

D;D;.;D;.

Vest4

0.74

MVP

0.80

MPC

1.7

ClinPred

0.72

GERP RS

5.8

Varity_R

0.70

gMVP

0.86

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over