chr17-30971093-G-C

Variant names:

• chr17-30971093-G-C
• rs1905865031
• NM_032322.4:c.20G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032322.4(RNF135):​c.20G>C​(p.Gly7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000289 in 1,382,016 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: RNF135 NM_032322.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.606
• Publications: 0 publications found

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

ACMG classification

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=0.14420724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF135	NM_032322.4	c.20G>C	p.Gly7Ala	missense_variant	Exon 1 of 5	ENST00000328381.10	NP_115698.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF135	ENST00000328381.10	c.20G>C	p.Gly7Ala	missense_variant	Exon 1 of 5	1	NM_032322.4	ENSP00000328340.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1382016 Hom.: 0 Cov.: 31 AF XY: 0.00000293 AC XY: 2 AN XY: 681868

African (AFR) AF: 0.00 AC: 0 AN: 31526

American (AMR) AF: 0.00 AC: 0 AN: 35630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25122

East Asian (EAS) AF: 0.00 AC: 0 AN: 35686

South Asian (SAS) AF: 0.00 AC: 0 AN: 79146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5518

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1078120

Other (OTH) AF: 0.00 AC: 0 AN: 57810

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 22, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.0032	T;T;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.49	T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.64	N;.;N;N
PhyloP100		0.61
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.74	N;.;N;N
REVEL	Benign	0.067
Sift	Benign	0.53	T;.;D;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.92	P;.;B;.
Vest4		0.17
MutPred		0.41		Gain of catalytic residue at G7 (P = 0.0775);Gain of catalytic residue at G7 (P = 0.0775);Gain of catalytic residue at G7 (P = 0.0775);Gain of catalytic residue at G7 (P = 0.0775);
MVP		0.54
MPC		0.10
ClinPred		0.21	T
GERP RS		1.8
PromoterAI		-0.0014	Neutral
Varity_R		0.029
gMVP		0.13
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs1905865031; hg19: chr17-29298111;