17-30971116-G-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_032322.4(RNF135):​c.43G>A​(p.Ala15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000521 in 1,534,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

RNF135
NM_032322.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.311

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 -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.058432728).
BS2
High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RNF135NM_032322.4 linkc.43G>A p.Ala15Thr 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.43G>A p.Ala15Thr missense_variant Exon 1 of 5 1 NM_032322.4 ENSP00000328340.5 Q8IUD6-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152184
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:
0.000578
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000782
AC:
1
AN:
127936
AF XY:
0.0000143
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:
0.0000211
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000362
AC:
5
AN:
1382016
Hom.:
0
Cov.:
31
AF XY:
0.00000440
AC XY:
3
AN XY:
681892
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31512
American (AMR)
AF:
0.00
AC:
0
AN:
35638
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25120
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35688
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79164
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
33460
Middle Eastern (MID)
AF:
0.000180
AC:
1
AN:
5542
European-Non Finnish (NFE)
AF:
0.00000186
AC:
2
AN:
1078088
Other (OTH)
AF:
0.0000346
AC:
2
AN:
57804
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.565
Heterozygous variant carriers
0
1
1
2
2
3
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:
0.0000197
AC:
3
AN:
152300
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74472
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41578
American (AMR)
AF:
0.00
AC:
0
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.000579
AC:
3
AN:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68002
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
1
2
2
3
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:
0.0000113
Asia WGS
AF:
0.000289
AC:
1
AN:
3476

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 19, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.43G>A (p.A15T) 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 43, causing the alanine (A) at amino acid position 15 to be replaced by a threonine (T). 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
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
12
DANN
Benign
0.90
DEOGEN2
Benign
0.0042
T;T;.;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.013
N
LIST_S2
Benign
0.62
T;T;T;T
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.058
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.13
N;.;N;N
PhyloP100
-0.31
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-0.33
N;.;N;N
REVEL
Benign
0.10
Sift
Benign
0.081
T;.;T;T
Sift4G
Uncertain
0.057
T;T;T;T
Polyphen
0.44
B;.;D;.
Vest4
0.023
MutPred
0.60
Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);
MVP
0.40
MPC
0.088
ClinPred
0.093
T
GERP RS
-2.5
PromoterAI
-0.017
Neutral
Varity_R
0.041
gMVP
0.10
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: rs1185685036; hg19: chr17-29298134; API