rs111902263

chr17-30971417-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032322.4(RNF135):c.344G>A(p.Arg115Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,516,774 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.014 (18 hom., cov: 33)
  • Exomes 𝑓: 0.020 (333 hom.)
• Consequence: RNF135 NM_032322.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.39

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030107498).
• BP6: Variant 17-30971417-G-A is Benign according to our data. Variant chr17-30971417-G-A is described in ClinVar as [Benign]. Clinvar id is 436548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-30971417-G-A is described in Lovd as [Benign]. Variant chr17-30971417-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0143 (2182/152310) while in subpopulation NFE AF= 0.0203 (1382/68020). AF 95% confidence interval is 0.0194. There are 18 homozygotes in gnomad4. There are 1048 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 2182 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF135	NM_032322.4	c.344G>A	p.Arg115Lys	missense_variant	1/5	ENST00000328381.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF135	ENST00000328381.10	c.344G>A	p.Arg115Lys	missense_variant	1/5	1	NM_032322.4	P1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2182 AN: 152200 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0257

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0124 AC: 1373 AN: 110488 Hom.: 20 AF XY: 0.0119 AC XY: 735 AN XY: 61648

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.00421

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000485

Gnomad FIN exome AF: 0.0241

Gnomad NFE exome AF: 0.0202

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.0197 AC: 26909 AN: 1364464 Hom.: 333 Cov.: 31 AF XY: 0.0192 AC XY: 12944 AN XY: 673386

Gnomad4 AFR exome AF: 0.00389

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.00397

Gnomad4 EAS exome AF: 0.0000302

Gnomad4 SAS exome AF: 0.000542

Gnomad4 FIN exome AF: 0.0264

Gnomad4 NFE exome AF: 0.0227

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0143 AC: 2182 AN: 152310 Hom.: 18 Cov.: 33 AF XY: 0.0141 AC XY: 1048 AN XY: 74466

Gnomad4 AFR AF: 0.00476

Gnomad4 AMR AF: 0.0177

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0257

Gnomad4 NFE AF: 0.0203

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0143 Hom.: 3

Bravo AF: 0.0138

TwinsUK AF: 0.0210 AC: 78

ALSPAC AF: 0.0234 AC: 90

ESP6500AA AF: 0.00302 AC: 6

ESP6500EA AF: 0.00764 AC: 31

ExAC AF: 0.00214 AC: 67

Asia WGS AF: 0.000578 AC: 2 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2020	This variant is associated with the following publications: (PMID: 26368817) -

RNF135-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	0.90
Dann	Benign	0.88
DEOGEN2	Benign	0.0037	T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0072	N
LIST_S2	Benign	0.41	T;T;T;T
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.13	N;.;N;N
REVEL	Benign	0.077
Sift	Benign	0.48	T;.;T;T
Sift4G	Benign	0.37	T;T;D;D
Polyphen		0.023	B;.;B;.
Vest4		0.039
MPC		0.095
ClinPred		0.0026	T
GERP RS		-0.71
Varity_R		0.084
gMVP		0.16

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: rs111902263; hg19: chr17-29298435; COSMIC: COSV100103891; COSMIC: COSV100103891;