17-30971395-T-C

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.322T>C(p.Ser108Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 1,522,404 control chromosomes in the GnomAD database, including 17,157 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 ( 9582 hom., cov: 33)

Exomes 𝑓: 0.025 ( 7575 hom. )

Consequence

RNF135
NM_032322.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.76

Publications

10 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=5.844231E-6).

BP6

Variant 17-30971395-T-C is Benign according to our data. Variant chr17-30971395-T-C is described in ClinVar as Benign. ClinVar VariationId is 1296606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032322.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RNF135	NM_032322.4	MANE Select	c.322T>C	p.Ser108Pro	missense	Exon 1 of 5	NP_115698.3
RNF135	NM_001184992.2		c.322T>C	p.Ser108Pro	missense	Exon 1 of 6	NP_001171921.1
RNF135	NM_197939.2		c.322T>C	p.Ser108Pro	missense	Exon 1 of 4	NP_922921.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RNF135	ENST00000328381.10	TSL:1 MANE Select	c.322T>C	p.Ser108Pro	missense	Exon 1 of 5	ENSP00000328340.5
RNF135	ENST00000535306.6	TSL:1	c.322T>C	p.Ser108Pro	missense	Exon 1 of 6	ENSP00000440470.2
RNF135	ENST00000324689.8	TSL:1	c.322T>C	p.Ser108Pro	missense	Exon 1 of 4	ENSP00000323693.4

Frequencies

GnomAD3 genomes

AF:

0.200

AC:

30338

AN:

152032

Hom.:

9551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.673

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0777

Gnomad ASJ

AF:

0.00923

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0300

Gnomad FIN

AF:

0.00697

Gnomad MID

AF:

0.0732

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.153

GnomAD2 exomes

AF:

0.0339

AC:

3896

AN:

114962

AF XY:

0.0303

show subpopulations

Gnomad AFR exome

AF:

0.694

Gnomad AMR exome

AF:

0.0391

Gnomad ASJ exome

AF:

0.00705

Gnomad EAS exome

AF:

0.000365

Gnomad FIN exome

AF:

0.00637

Gnomad NFE exome

AF:

0.00936

Gnomad OTH exome

AF:

0.0262

GnomAD4 exome

AF:

0.0250

AC:

34240

AN:

1370264

Hom.:

7575

Cov.:

AF XY:

0.0233

AC XY:

15787

AN XY:

676426

show subpopulations

African (AFR)

AF:

0.701

AC:

19980

AN:

28486

American (AMR)

AF:

0.0461

AC:

1590

AN:

34468

Ashkenazi Jewish (ASJ)

AF:

0.00723

AC:

178

AN:

24604

East Asian (EAS)

AF:

0.0000893

AC:

AN:

33580

South Asian (SAS)

AF:

0.0282

AC:

2195

AN:

77848

European-Finnish (FIN)

AF:

0.00600

AC:

222

AN:

37004

Middle Eastern (MID)

AF:

0.0538

AC:

216

AN:

4016

European-Non Finnish (NFE)

AF:

0.00637

AC:

6841

AN:

1073202

Other (OTH)

AF:

0.0528

AC:

3015

AN:

57056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1189

2379

3568

4758

5947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

584

1168

1752

2336

2920

<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:

0.200

AC:

30414

AN:

152140

Hom.:

9582

Cov.:

AF XY:

0.193

AC XY:

14382

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.673

AC:

27931

AN:

41498

American (AMR)

AF:

0.0775

AC:

1185

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00923

AC:

AN:

3468

East Asian (EAS)

AF:

0.000581

AC:

AN:

5162

South Asian (SAS)

AF:

0.0288

AC:

139

AN:

4826

European-Finnish (FIN)

AF:

0.00697

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0103

AC:

703

AN:

67976

Other (OTH)

AF:

0.151

AC:

318

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

604

1207

1811

2414

3018

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<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:

0.0889

Hom.:

1449

Bravo

AF:

0.224

ESP6500AA

AF:

0.378

AC:

1011

ESP6500EA

AF:

0.00561

AC:

ExAC

AF:

0.0305

AC:

1412

Asia WGS

AF:

0.0530

AC:

186

AN:

3470

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.88

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.011

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00037

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0000058

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.3

PhyloP100

-1.8

PrimateAI

Uncertain

0.70

PROVEAN

Benign

1.1

REVEL

Benign

0.038

Sift

Benign

0.34

Sift4G

Benign

0.42

Polyphen

0.0

Vest4

0.088

MPC

0.11

ClinPred

0.0069

GERP RS

1.7

PromoterAI

-0.076

Neutral

(source)

Varity_R

0.057

gMVP

0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over