rs370242930

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PP3_ModeratePP5BS2

The NM_017831.4(RNF125):c.520C>T(p.Arg174Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,611,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R174L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

RNF125
NM_017831.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided P:1U:1

Conservation

PhyloP100: 2.58

Publications

3 publications found

Variant links:

Genes affected

RNF125 (HGNC:21150): (ring finger protein 125) This gene encodes a novel E3 ubiquitin ligase that contains a RING finger domain in the N-terminus and three zinc-binding and one ubiquitin-interacting motif in the C-terminus. As a result of myristoylation, this protein associates with membranes and is primarily localized to intracellular membrane systems. The encoded protein may function as a positive regulator in the T-cell receptor signaling pathway. [provided by RefSeq, Mar 2012]

RNF125 Gene-Disease associations (from GenCC):

Tenorio syndrome
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

RNF125 links:

ENSG00000263917 (HGNC:):

ENSG00000263917 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

PP5

Variant 18-32065917-C-T is Pathogenic according to our data. Variant chr18-32065917-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 183422.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF125	NM_017831.4 link	c.520C>T	p.Arg174Cys	missense_variant	Exon 5 of 6	ENST00000217740.4	NP_060301.2	Q96EQ8
RNF125	NM_001436860.1 link	c.520C>T	p.Arg174Cys	missense_variant	Exon 5 of 6		NP_001423789.1
RNF125	NM_001436861.1 link	c.504+20185C>T		intron_variant	Intron 4 of 4		NP_001423790.1
RNF125	XM_011526046.4 link	c.505-2381C>T		intron_variant	Intron 4 of 4		XP_011524348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF125	ENST00000217740.4 link	c.520C>T	p.Arg174Cys	missense_variant	Exon 5 of 6	1	NM_017831.4	ENSP00000217740.3		Q96EQ8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152114

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251308

AF XY:

0.0000295

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1459312

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000811

AC:

AN:

1109792

Other (OTH)

AF:

0.00

AC:

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Tenorio syndrome

Pathogenic:1

Dec 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

RNF125-related disorder

Uncertain:1

Apr 15, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RNF125 c.520C>T variant is predicted to result in the amino acid substitution p.Arg174Cys. This variant was reported in multiple individuals with Tenorio syndrome (OMIM #616260; Tenorio et al. 2014. PubMed ID: 25196541; Tenorio-Castaño et al. 2021. PubMed ID: 34196401). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.3

PhyloP100

2.6

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.10

REVEL

Pathogenic

0.75

Sift

Benign

0.066

Sift4G

Uncertain

0.0090

Polyphen

0.99

Vest4

0.83

MVP

0.89

MPC

1.0

ClinPred

0.57

GERP RS

5.8

Varity_R

0.19

gMVP

0.67

Mutation Taster

=73/27

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over