Genetic Variant RNF135:p.Glu46Asp (chr17-30971211-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032322.4(RNF135):c.138G>C(p.Glu46Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,361,426 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

RNF135
NM_032322.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.310

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08334857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF135	NM_032322.4 link	c.138G>C	p.Glu46Asp	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.138G>C	p.Glu46Asp	missense_variant	Exon 1 of 5	1	NM_032322.4	ENSP00000328340.5		Q8IUD6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.35e-7

AC:

AN:

1361426

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

671504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27866

American (AMR)

AF:

0.00

AC:

AN:

33048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24174

East Asian (EAS)

AF:

0.00

AC:

AN:

33224

South Asian (SAS)

AF:

0.00

AC:

AN:

76868

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34756

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4562

European-Non Finnish (NFE)

AF:

9.34e-7

AC:

AN:

1070222

Other (OTH)

AF:

0.00

AC:

AN:

56706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.138G>C (p.E46D) alteration is located in exon 1 (coding exon 1) of the RNF135 gene. This alteration results from a G to C substitution at nucleotide position 138, causing the glutamic acid (E) at amino acid position 46 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

1.9

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.0037

T;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.19

T;T;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.083

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.;L;L

PhyloP100

-0.31

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.83

N;.;N;N

REVEL

Benign

0.095

Sift

Benign

0.62

T;.;T;T

Sift4G

Benign

0.33

T;T;T;T

Polyphen

0.14

B;.;P;.

Vest4

0.16

MutPred

0.60

Gain of MoRF binding (P = 0.123);Gain of MoRF binding (P = 0.123);Gain of MoRF binding (P = 0.123);Gain of MoRF binding (P = 0.123);

MVP

0.32

MPC

0.083

ClinPred

0.32

GERP RS

-4.7

PromoterAI

-0.14

Neutral

(source)

Varity_R

0.072

gMVP

0.22

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over