Variant 6-127287611-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001242850.2(RNF146):c.998G>A(p.Arg333Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

RNF146
NM_001242850.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04314035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF146	NM_001242850.2 linkuse as main transcript	c.998G>A	p.Arg333Gln	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.998G>A	p.Arg333Gln	missense_variant	3/3	2	NM_001242850.2	ENSP00000357297.1	Q9NTX7-1
RNF146	ENST00000610153.1 linkuse as main transcript	c.998G>A	p.Arg333Gln	missense_variant	3/3	2		ENSP00000476814.1	Q9NTX7-1
RNF146	ENST00000608991.5 linkuse as main transcript	c.995G>A	p.Arg332Gln	missense_variant	5/5	4		ENSP00000477168.1	Q9NTX7-2
RNF146	ENST00000356799.6 linkuse as main transcript	c.*1003G>A		3_prime_UTR_variant	4/4	2		ENSP00000349253.3	V9GYY4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

249908

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

135024

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460896

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726784

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Oct 08, 2024

The c.998G>A (p.R333Q) alteration is located in exon 3 (coding exon 2) of the RNF146 gene. This alteration results from a G to A substitution at nucleotide position 998, causing the arginine (R) at amino acid position 333 to be replaced by a glutamine (Q). 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

0.080

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.024

T;T;.;T;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.75

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.77

.;T;T;.;.

M_CAP

Benign

0.0053

MetaRNN

Benign

0.043

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

L;L;.;L;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.32

N;.;N;.;.

REVEL

Benign

0.10

Sift

Benign

0.047

D;.;D;.;.

Sift4G

Benign

0.27

.;.;T;.;T

Polyphen

0.0

B;B;.;B;.

Vest4

0.079

MutPred

0.31

Loss of MoRF binding (P = 0.0287);Loss of MoRF binding (P = 0.0287);.;Loss of MoRF binding (P = 0.0287);.;

MVP

0.18

MPC

0.50

ClinPred

0.084

GERP RS

-0.59

Varity_R

0.052

gMVP

0.29

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