17-30971419-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_032322.4(RNF135):c.346C>T(p.Pro116Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000154 in 1,363,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.000015 (0 hom.)
• Consequence: RNF135 NM_032322.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.56

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049168706).
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF135	NM_032322.4	c.346C>T	p.Pro116Ser	missense_variant	1/5	ENST00000328381.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF135	ENST00000328381.10	c.346C>T	p.Pro116Ser	missense_variant	1/5	1	NM_032322.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000454 AC: 5 AN: 110026 Hom.: 0 AF XY: 0.0000489 AC XY: 3 AN XY: 61408

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 SAS exome AF: 0.000243

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000154 AC: 21 AN: 1363504 Hom.: 0 Cov.: 31 AF XY: 0.0000163 AC XY: 11 AN XY: 672882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000194

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000560

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.000100 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The c.346C>T (p.P116S) alteration is located in exon 1 (coding exon 1) of the RNF135 gene. This alteration results from a C to T substitution at nucleotide position 346, causing the proline (P) at amino acid position 116 to be replaced by a serine (S). 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	0.081
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.43
Dann	Benign	0.88
DEOGEN2	Benign	0.0033	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.43	T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.049	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.95	L;.;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N;.;N;N
REVEL	Benign	0.027
Sift	Benign	0.26	T;.;T;T
Sift4G	Benign	0.99	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.038
MutPred		0.23		Gain of phosphorylation at P116 (P = 0.0013);Gain of phosphorylation at P116 (P = 0.0013);Gain of phosphorylation at P116 (P = 0.0013);Gain of phosphorylation at P116 (P = 0.0013);
MVP		0.25
MPC		0.091
ClinPred		0.028	T
GERP RS		-3.0
Varity_R		0.035
gMVP		0.11

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

LitVar

Other links and lift over

dbSNP: rs765680585; hg19: chr17-29298437;