17-30971198-G-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_032322.4(RNF135):​c.125G>A​(p.Arg42His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,523,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R42C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

RNF135
NM_032322.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.899

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10985035).
BS2
High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RNF135NM_032322.4 linkc.125G>A p.Arg42His 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
RNF135ENST00000328381.10 linkc.125G>A p.Arg42His missense_variant Exon 1 of 5 1 NM_032322.4 ENSP00000328340.5 Q8IUD6-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152166
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000426
AC:
5
AN:
117298
AF XY:
0.0000463
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000233
AC:
32
AN:
1371754
Hom.:
0
Cov.:
31
AF XY:
0.0000310
AC XY:
21
AN XY:
676612
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
29256
American (AMR)
AF:
0.00
AC:
0
AN:
35026
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24660
East Asian (EAS)
AF:
0.00
AC:
0
AN:
34412
South Asian (SAS)
AF:
0.000205
AC:
16
AN:
78010
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
34130
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4698
European-Non Finnish (NFE)
AF:
0.0000121
AC:
13
AN:
1074292
Other (OTH)
AF:
0.0000524
AC:
3
AN:
57270
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.533
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000131
AC:
2
AN:
152166
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74348
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41456
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67998
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000548
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 12, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.125G>A (p.R42H) alteration is located in exon 1 (coding exon 1) of the RNF135 gene. This alteration results from a G to A substitution at nucleotide position 125, causing the arginine (R) at amino acid position 42 to be replaced by a histidine (H). 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
0.11
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.010
T;T;.;.
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.49
FATHMM_MKL
Benign
0.028
N
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.11
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.3
L;.;L;L
PhyloP100
-0.90
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-2.2
N;.;N;N
REVEL
Benign
0.091
Sift
Benign
0.13
T;.;D;D
Sift4G
Uncertain
0.041
D;D;D;D
Polyphen
1.0
D;.;D;.
Vest4
0.079
MutPred
0.69
Loss of MoRF binding (P = 0.0933);Loss of MoRF binding (P = 0.0933);Loss of MoRF binding (P = 0.0933);Loss of MoRF binding (P = 0.0933);
MVP
0.18
MPC
0.11
ClinPred
0.61
D
GERP RS
-0.18
PromoterAI
-0.084
Neutral
Varity_R
0.059
gMVP
0.22
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs774526846; hg19: chr17-29298216; API