rs111902263

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032322.4(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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 18 hom., cov: 33)

Exomes 𝑓: 0.020 ( 333 hom. )

Consequence

RNF135
NM_032322.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.39

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

overgrowth-macrocephaly-facial dysmorphism syndrome
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
overgrowth syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RNF135 links:

ENSG00000264456 (HGNC:):

ENSG00000264456 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 436548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2182 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF135	NM_032322.4 link	c.344G>A	p.Arg115Lys	missense_variant	Exon 1 of 5	ENST00000328381.10	NP_115698.3	Q8IUD6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF135	ENST00000328381.10 link	c.344G>A	p.Arg115Lys	missense_variant	Exon 1 of 5	1	NM_032322.4	ENSP00000328340.5		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

GnomAD2 exomes

AF:

0.0124

AC:

1373

AN:

110488

AF XY:

0.0119

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 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

African (AFR)

AF:

0.00389

AC:

109

AN:

28052

American (AMR)

AF:

0.0132

AC:

450

AN:

33974

Ashkenazi Jewish (ASJ)

AF:

0.00397

AC:

AN:

24440

East Asian (EAS)

AF:

0.0000302

AC:

AN:

33140

South Asian (SAS)

AF:

0.000542

AC:

AN:

77490

European-Finnish (FIN)

AF:

0.0264

AC:

925

AN:

35068

Middle Eastern (MID)

AF:

0.00300

AC:

AN:

4000

European-Non Finnish (NFE)

AF:

0.0227

AC:

24325

AN:

1071488

Other (OTH)

AF:

0.0167

AC:

948

AN:

56812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1775

3550

5326

7101

8876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

944

1888

2832

3776

4720

<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:

0.0143

AC:

2182

AN:

152310

Hom.:

Cov.:

AF XY:

0.0141

AC XY:

1048

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00476

AC:

198

AN:

41572

American (AMR)

AF:

0.0177

AC:

271

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0257

AC:

273

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0203

AC:

1382

AN:

68020

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

116

233

349

466

582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0140

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26368817) -

not specified

Benign:2

Mar 23, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 28, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RNF135-related disorder

Benign:1

Apr 13, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

-1.4

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

PromoterAI

-0.22

Neutral

(source)

Varity_R

0.084

gMVP

0.16

Mutation Taster

=100/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over