dbSNP rs570839353: RNF135:p.His43Gln (chr17-30971202-C-G) – 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.129C>G(p.His43Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,371,792 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H43H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

RNF135
NM_032322.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.614

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=0.120194465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF135	NM_032322.4 link	c.129C>G	p.His43Gln	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.129C>G	p.His43Gln	missense_variant	Exon 1 of 5	1	NM_032322.4	ENSP00000328340.5		Q8IUD6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.29e-7

AC:

AN:

1371792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

676668

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29178

American (AMR)

AF:

0.0000286

AC:

AN:

35002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24656

East Asian (EAS)

AF:

0.00

AC:

AN:

34404

South Asian (SAS)

AF:

0.00

AC:

AN:

78008

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074242

Other (OTH)

AF:

0.00

AC:

AN:

57276

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

1.3

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0014

T;T;.;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.68

T;T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.035

N;.;N;N

PhyloP100

0.61

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.32

N;.;N;N

REVEL

Benign

0.054

Sift

Benign

0.59

T;.;T;T

Sift4G

Benign

0.58

T;T;T;T

Polyphen

0.0010

B;.;B;.

Vest4

0.090

MutPred

0.41

Gain of MoRF binding (P = 0.1539);Gain of MoRF binding (P = 0.1539);Gain of MoRF binding (P = 0.1539);Gain of MoRF binding (P = 0.1539);

MVP

0.16

MPC

0.090

ClinPred

0.13

GERP RS

1.3

PromoterAI

-0.049

Neutral

(source)

Varity_R

0.058

gMVP

0.081

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

Computational scores

Splicing

Publications

Other links and lift over