17-30971372-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_032322.4(RNF135):c.299A>G(p.His100Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,527,714 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 28 hom. )

Consequence

RNF135
NM_032322.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.202

Publications

3 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003282249).

BP6

Variant 17-30971372-A-G is Benign according to our data. Variant chr17-30971372-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 573 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF135	NM_032322.4 link	c.299A>G	p.His100Arg	missense_variant	Exon 1 of 5	ENST00000328381.10	NP_115698.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF135	ENST00000328381.10 link	c.299A>G	p.His100Arg	missense_variant	Exon 1 of 5	1	NM_032322.4	ENSP00000328340.5

Frequencies

GnomAD3 genomes

AF:

0.00377

AC:

574

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0105

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00546

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00337

AC:

394

AN:

117010

AF XY:

0.00322

show subpopulations

Gnomad AFR exome

AF:

0.000712

Gnomad AMR exome

AF:

0.000349

Gnomad ASJ exome

AF:

0.000663

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0124

Gnomad NFE exome

AF:

0.00530

Gnomad OTH exome

AF:

0.00308

GnomAD4 exome

AF:

0.00533

AC:

7335

AN:

1375538

Hom.:

Cov.:

AF XY:

0.00523

AC XY:

3551

AN XY:

678924

show subpopulations

African (AFR)

AF:

0.000937

AC:

AN:

28824

American (AMR)

AF:

0.000487

AC:

AN:

34910

Ashkenazi Jewish (ASJ)

AF:

0.000445

AC:

AN:

24736

East Asian (EAS)

AF:

0.00

AC:

AN:

34124

South Asian (SAS)

AF:

0.00187

AC:

146

AN:

78234

European-Finnish (FIN)

AF:

0.0112

AC:

435

AN:

38912

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

4036

European-Non Finnish (NFE)

AF:

0.00602

AC:

6472

AN:

1074524

Other (OTH)

AF:

0.00384

AC:

220

AN:

57238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

476

952

1429

1905

2381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

256

512

768

1024

1280

<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:

0.00377

AC:

573

AN:

152176

Hom.:

Cov.:

AF XY:

0.00362

AC XY:

269

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41540

American (AMR)

AF:

0.00222

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.00104

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0105

AC:

112

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00546

AC:

371

AN:

67966

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00532

Hom.:

Bravo

AF:

0.00309

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00202

AC:

ExAC

AF:

0.000998

AC:

Asia WGS

AF:

0.000290

AC:

AN:

3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RNF135: BS1, BS2 -

Aug 10, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 30, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jan 09, 2019

Genetic Services Laboratory, University of Chicago

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

0.056

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.16

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.0023

T;T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.28

T;T;T;T

M_CAP

Benign

0.0045

MetaRNN

Benign

0.0033

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;.;N;N

PhyloP100

-0.20

PrimateAI

Uncertain

0.74

PROVEAN

Benign

0.61

N;.;N;N

REVEL

Benign

0.012

Sift

Benign

0.20

T;.;T;T

Sift4G

Benign

0.57

T;T;T;T

Polyphen

0.0

B;.;B;.

Vest4

0.054

MVP

0.30

MPC

0.11

ClinPred

0.015

GERP RS

-1.2

PromoterAI

-0.070

Neutral

(source)

Varity_R

0.033

gMVP

0.049

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