Genetic Variant RNF135:p.Gly26Ala (chr17-30971150-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.77G>C(p.Gly26Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,381,644 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: 0.0000014 ( 0 hom. )

Consequence

RNF135
NM_032322.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0460

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:

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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=0.074988365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF135	NM_032322.4 link	c.77G>C	p.Gly26Ala	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.77G>C	p.Gly26Ala	missense_variant	Exon 1 of 5	1	NM_032322.4	ENSP00000328340.5		Q8IUD6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1381644

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

681690

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31492

American (AMR)

AF:

0.00

AC:

AN:

35630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25114

East Asian (EAS)

AF:

0.00

AC:

AN:

35674

South Asian (SAS)

AF:

0.00

AC:

AN:

79148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5390

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1077942

Other (OTH)

AF:

0.00

AC:

AN:

57774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.77G>C (p.G26A) 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 77, causing the glycine (G) at amino acid position 26 to be replaced by an alanine (A). 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

0.16

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.0042

T;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.80

T;T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.075

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.;L;L

PhyloP100

-0.046

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.81

N;.;N;N

REVEL

Benign

0.10

Sift

Benign

0.37

T;.;D;D

Sift4G

Benign

0.35

T;T;T;T

Polyphen

0.34

B;.;P;.

Vest4

0.088

MutPred

0.54

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.16

MPC

0.20

ClinPred

0.20

GERP RS

-3.1

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.046

gMVP

0.18

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over