Variant 6-127287551-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001242850.2(RNF146):c.938T>G(p.Leu313Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,461,182 control chromosomes in the GnomAD database, with no homozygous occurrence. 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.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

RNF146
NM_001242850.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.104784966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF146	NM_001242850.2 linkuse as main transcript	c.938T>G	p.Leu313Arg	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.938T>G	p.Leu313Arg	missense_variant	3/3	2	NM_001242850.2	ENSP00000357297.1	Q9NTX7-1
RNF146	ENST00000610153.1 linkuse as main transcript	c.938T>G	p.Leu313Arg	missense_variant	3/3	2		ENSP00000476814.1	Q9NTX7-1
RNF146	ENST00000608991.5 linkuse as main transcript	c.935T>G	p.Leu312Arg	missense_variant	5/5	4		ENSP00000477168.1	Q9NTX7-2
RNF146	ENST00000356799.6 linkuse as main transcript	c.*943T>G		3_prime_UTR_variant	4/4	2		ENSP00000349253.3	V9GYY4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249776

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134960

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1461182

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726916

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Aug 20, 2024

The c.938T>G (p.L313R) alteration is located in exon 3 (coding exon 2) of the RNF146 gene. This alteration results from a T to G substitution at nucleotide position 938, causing the leucine (L) at amino acid position 313 to be replaced by an arginine (R). 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

0.063

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.022

T;T;.;T;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

.;T;T;.;.

M_CAP

Benign

0.0055

MetaRNN

Benign

0.10

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L;.;L;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.62

N;.;N;.;.

REVEL

Benign

0.13

Sift

Benign

0.49

T;.;T;.;.

Sift4G

Benign

0.49

.;.;T;.;T

Polyphen

0.010

B;B;.;B;.

Vest4

0.37

MutPred

0.27

Gain of MoRF binding (P = 0.0065);Gain of MoRF binding (P = 0.0065);.;Gain of MoRF binding (P = 0.0065);.;

MVP

0.20

MPC

0.73

ClinPred

0.039

GERP RS

1.3

Varity_R

0.075

gMVP

0.14

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