Genetic Variant RNF146:c.3-1173T>C (chr6-127285443-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001242850.2(RNF146):c.3-1173T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.747 in 573,868 control chromosomes in the GnomAD database, including 160,273 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.73 ( 40486 hom., cov: 29)

Exomes 𝑓: 0.75 ( 119787 hom. )

Consequence

RNF146
NM_001242850.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.797

Publications

15 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.04).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242850.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RNF146	NM_001242850.2	MANE Select	c.3-1173T>C	intron	N/A	NP_001229779.1	Q9NTX7-1
RNF146	NM_001242849.2		c.3-1173T>C	intron	N/A	NP_001229778.1	Q9NTX7-1
RNF146	NM_001242851.1		c.3-1173T>C	intron	N/A	NP_001229780.1	Q9NTX7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RNF146	ENST00000368314.6	TSL:2 MANE Select	c.3-1173T>C	intron	N/A	ENSP00000357297.1	Q9NTX7-1
RNF146	ENST00000610153.1	TSL:2	c.3-1173T>C	intron	N/A	ENSP00000476814.1	Q9NTX7-1
RNF146	ENST00000911117.1		c.3-1173T>C	intron	N/A	ENSP00000581176.1

Frequencies

GnomAD3 genomes

AF:

0.730

AC:

110350

AN:

151156

Hom.:

40460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.690

Gnomad AMI

AF:

0.720

Gnomad AMR

AF:

0.752

Gnomad ASJ

AF:

0.762

Gnomad EAS

AF:

0.780

Gnomad SAS

AF:

0.620

Gnomad FIN

AF:

0.723

Gnomad MID

AF:

0.737

Gnomad NFE

AF:

0.753

Gnomad OTH

AF:

0.754

GnomAD4 exome

AF:

0.753

AC:

318393

AN:

422596

Hom.:

119787

AF XY:

0.752

AC XY:

150110

AN XY:

199720

show subpopulations

African (AFR)

AF:

0.678

AC:

5163

AN:

7620

American (AMR)

AF:

0.719

AC:

318

AN:

442

Ashkenazi Jewish (ASJ)

AF:

0.774

AC:

2041

AN:

2636

East Asian (EAS)

AF:

0.783

AC:

1344

AN:

1716

South Asian (SAS)

AF:

0.645

AC:

5244

AN:

8132

European-Finnish (FIN)

AF:

0.773

AC:

102

AN:

132

Middle Eastern (MID)

AF:

0.697

AC:

584

AN:

838

European-Non Finnish (NFE)

AF:

0.757

AC:

293221

AN:

387214

Other (OTH)

AF:

0.748

AC:

10376

AN:

13866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

3783

7566

11348

15131

18914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9710

19420

29130

38840

48550

<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:

0.730

AC:

110424

AN:

151272

Hom.:

40486

Cov.:

AF XY:

0.724

AC XY:

53479

AN XY:

73840

show subpopulations

African (AFR)

AF:

0.690

AC:

28442

AN:

41232

American (AMR)

AF:

0.751

AC:

11386

AN:

15156

Ashkenazi Jewish (ASJ)

AF:

0.762

AC:

2637

AN:

3460

East Asian (EAS)

AF:

0.780

AC:

3979

AN:

5104

South Asian (SAS)

AF:

0.620

AC:

2975

AN:

4802

European-Finnish (FIN)

AF:

0.723

AC:

7539

AN:

10432

Middle Eastern (MID)

AF:

0.738

AC:

217

AN:

294

European-Non Finnish (NFE)

AF:

0.753

AC:

51014

AN:

67784

Other (OTH)

AF:

0.753

AC:

1580

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1434

2868

4303

5737

7171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

836

1672

2508

3344

4180

<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:

0.734

Hom.:

7814

Bravo

AF:

0.734

Asia WGS

AF:

0.689

AC:

2397

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.7

(source)

DANN

Benign

0.54

PhyloP100

-0.80

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over