17-30971417-G-A

Position:

chr17-30971417-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000328381.10(RNF135):c.344G>A(p.Arg115Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,516,774 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.014 ( 18 hom., cov: 33)

Exomes 𝑓: 0.020 ( 333 hom. )

Consequence

RNF135
ENST00000328381.10 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.39

Variant links:

Genes affected

RNF135 (HGNC:21158): (ring finger protein 135) The protein encoded by this gene contains a RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. This gene is located in a chromosomal region known to be frequently deleted in patients with neurofibromatosis. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

RNF135 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030107498).

BP6

Variant 17-30971417-G-A is Benign according to our data. Variant chr17-30971417-G-A is described in ClinVar as [Benign]. Clinvar id is 436548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-30971417-G-A is described in Lovd as [Benign]. Variant chr17-30971417-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0143 (2182/152310) while in subpopulation NFE AF= 0.0203 (1382/68020). AF 95% confidence interval is 0.0194. There are 18 homozygotes in gnomad4. There are 1048 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2182 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF135	NM_032322.4 linkuse as main transcript	c.344G>A	p.Arg115Lys	missense_variant	1/5	ENST00000328381.10	NP_115698.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF135	ENST00000328381.10 linkuse as main transcript	c.344G>A	p.Arg115Lys	missense_variant	1/5	1	NM_032322.4	ENSP00000328340	P1	Q8IUD6-1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2182

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00478

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0257

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0203

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0124

AC:

1373

AN:

110488

Hom.:

AF XY:

0.0119

AC XY:

735

AN XY:

61648

show subpopulations

Gnomad AFR exome

AF:

0.0101

Gnomad AMR exome

AF:

0.0127

Gnomad ASJ exome

AF:

0.00421

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000485

Gnomad FIN exome

AF:

0.0241

Gnomad NFE exome

AF:

0.0202

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.0197

AC:

26909

AN:

1364464

Hom.:

333

Cov.:

AF XY:

0.0192

AC XY:

12944

AN XY:

673386

show subpopulations

Gnomad4 AFR exome

AF:

0.00389

Gnomad4 AMR exome

AF:

0.0132

Gnomad4 ASJ exome

AF:

0.00397

Gnomad4 EAS exome

AF:

0.0000302

Gnomad4 SAS exome

AF:

0.000542

Gnomad4 FIN exome

AF:

0.0264

Gnomad4 NFE exome

AF:

0.0227

Gnomad4 OTH exome

AF:

0.0167

GnomAD4 genome

AF:

0.0143

AC:

2182

AN:

152310

Hom.:

Cov.:

AF XY:

0.0141

AC XY:

1048

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00476

Gnomad4 AMR

AF:

0.0177

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0257

Gnomad4 NFE

AF:

0.0203

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0143

Hom.:

Bravo

AF:

0.0138

TwinsUK

AF:

0.0210

AC:

ALSPAC

AF:

0.0234

AC:

ESP6500AA

AF:

0.00302

AC:

ESP6500EA

AF:

0.00764

AC:

ExAC

AF:

0.00214

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2020	This variant is associated with the following publications: (PMID: 26368817) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2017	- -

RNF135-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.90

DANN

Benign

0.88

DEOGEN2

Benign

0.0037

T;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0072

LIST_S2

Benign

0.41

T;T;T;T

MetaRNN

Benign

0.0030

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.;L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.13

N;.;N;N

REVEL

Benign

0.077

Sift

Benign

0.48

T;.;T;T

Sift4G

Benign

0.37

T;T;D;D

Polyphen

0.023

B;.;B;.

Vest4

0.039

MPC

0.095

ClinPred

0.0026

GERP RS

-0.71

Varity_R

0.084

gMVP

0.16

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