chr17-30971089-C-G

Variant names:

• chr17-30971089-C-G
• rs1167074464
• NM_032322.4:c.16C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032322.4(RNF135):​c.16C>G​(p.Leu6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,382,014 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: 7.2e-7 (0 hom.)
• Consequence: RNF135 NM_032322.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.86
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040383816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF135	NM_032322.4	c.16C>G	p.Leu6Val	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.16C>G	p.Leu6Val	missense_variant	Exon 1 of 5	1	NM_032322.4	ENSP00000328340.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1382014 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 681874

African (AFR) AF: 0.00 AC: 0 AN: 31520

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25118

East Asian (EAS) AF: 0.00 AC: 0 AN: 35690

South Asian (SAS) AF: 0.00 AC: 0 AN: 79140

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5528

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1078116

Other (OTH) AF: 0.00 AC: 0 AN: 57814

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16C>G (p.L6V) alteration is located in exon 1 (coding exon 1) of the RNF135 gene. This alteration results from a C to G substitution at nucleotide position 16, causing the leucine (L) at amino acid position 6 to be replaced by a valine (V). 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	0.078
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.0070
DANN	Benign	0.45
DEOGEN2	Benign	0.0047	T;T;.;.
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.0050	N
LIST_S2	Benign	0.31	T;T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.040	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.11	N;.;N;N
PhyloP100		-4.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.080	N;D;N;N
REVEL	Benign	0.030
Sift	Benign	0.36	T;D;T;T
Sift4G	Benign	0.67	T;T;T;T
Polyphen		0.0050	B;.;B;.
Vest4		0.055
MutPred		0.66		Gain of catalytic residue at L6 (P = 0.1898);Gain of catalytic residue at L6 (P = 0.1898);Gain of catalytic residue at L6 (P = 0.1898);Gain of catalytic residue at L6 (P = 0.1898);
MVP		0.16
MPC		0.090
ClinPred		0.47	T
GERP RS		-7.8
PromoterAI		-0.31	Neutral
Varity_R		0.034
gMVP		0.10
Mutation Taster		=98/2	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: rs1167074464; hg19: chr17-29298107;