17-30971286-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032322.4(RNF135):c.213C>G(p.His71Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,527,428 control chromosomes in the GnomAD database, including 17,184 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 0.20 ( 9664 hom., cov: 33)

Exomes 𝑓: 0.025 ( 7520 hom. )

Consequence

RNF135
NM_032322.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0860

Publications

13 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:

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=2.7195128E-6).

BP6

Variant 17-30971286-C-G is Benign according to our data. Variant chr17-30971286-C-G is described in ClinVar as [Benign]. Clinvar id is 1232153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF135	NM_032322.4 link	c.213C>G	p.His71Gln	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.213C>G	p.His71Gln	missense_variant	Exon 1 of 5	1	NM_032322.4	ENSP00000328340.5		Q8IUD6-1

Frequencies

GnomAD3 genomes

AF:

0.200

AC:

30444

AN:

152170

Hom.:

9630

Cov.:

show subpopulations

Gnomad AFR

AF:

0.674

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0788

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0298

Gnomad FIN

AF:

0.00697

Gnomad MID

AF:

0.0860

Gnomad NFE

AF:

0.0103

Gnomad OTH

AF:

0.152

GnomAD2 exomes

AF:

0.0312

AC:

3707

AN:

118684

AF XY:

0.0277

show subpopulations

Gnomad AFR exome

AF:

0.687

Gnomad AMR exome

AF:

0.0387

Gnomad ASJ exome

AF:

0.00713

Gnomad EAS exome

AF:

0.000352

Gnomad FIN exome

AF:

0.00620

Gnomad NFE exome

AF:

0.00930

Gnomad OTH exome

AF:

0.0270

GnomAD4 exome

AF:

0.0248

AC:

34146

AN:

1375150

Hom.:

7520

Cov.:

AF XY:

0.0232

AC XY:

15750

AN XY:

678724

show subpopulations

African (AFR)

AF:

0.701

AC:

19751

AN:

28176

American (AMR)

AF:

0.0465

AC:

1601

AN:

34430

Ashkenazi Jewish (ASJ)

AF:

0.00727

AC:

179

AN:

24630

East Asian (EAS)

AF:

0.0000888

AC:

AN:

33790

South Asian (SAS)

AF:

0.0280

AC:

2179

AN:

77722

European-Finnish (FIN)

AF:

0.00596

AC:

249

AN:

41772

Middle Eastern (MID)

AF:

0.0582

AC:

241

AN:

4140

European-Non Finnish (NFE)

AF:

0.00643

AC:

6899

AN:

1073406

Other (OTH)

AF:

0.0533

AC:

3044

AN:

57084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1252

2505

3757

5010

6262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.200

AC:

30522

AN:

152278

Hom.:

9664

Cov.:

AF XY:

0.194

AC XY:

14474

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.675

AC:

28020

AN:

41534

American (AMR)

AF:

0.0786

AC:

1203

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.0286

AC:

138

AN:

4832

European-Finnish (FIN)

AF:

0.00697

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0788

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0103

AC:

702

AN:

68018

Other (OTH)

AF:

0.150

AC:

318

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

605

1210

1816

2421

3026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0170

Hom.:

282

Bravo

AF:

0.224

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.398

AC:

1145

ESP6500EA

AF:

0.00646

AC:

ExAC

AF:

0.0307

AC:

2135

Asia WGS

AF:

0.0540

AC:

187

AN:

3464

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

4.7

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.0047

T;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0020

LIST_S2

Benign

0.063

T;T;T;T

MetaRNN

Benign

0.0000027

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.1

N;.;N;N

PhyloP100

-0.086

PrimateAI

Uncertain

0.74

PROVEAN

Benign

1.1

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.76

T;D;T;T

Sift4G

Benign

0.72

T;T;T;T

Polyphen

0.0

B;.;B;.

Vest4

0.059

MutPred

0.12

Gain of ubiquitination at K74 (P = 0.0545);Gain of ubiquitination at K74 (P = 0.0545);Gain of ubiquitination at K74 (P = 0.0545);Gain of ubiquitination at K74 (P = 0.0545);

MPC

0.090

ClinPred

0.0033

GERP RS

3.5

PromoterAI

0.25

Neutral

(source)

Varity_R

0.047

gMVP

0.056

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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17-30971286-C-G

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