rs7225888

chr17-30971286-C-Gchr17-30971286-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_032322.4(RNF135):c.213C>G(p.His71Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,527,428 control chromosomes in the GnomAD database, including 17,184 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 0.20 (9664 hom., cov: 33)
  • Exomes 𝑓: 0.025 (7520 hom.)
• Consequence: RNF135 NM_032322.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0860

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.7195128E-6).
• BP6: Variant 17-30971286-C-G is Benign according to our data. Variant chr17-30971286-C-G is described in ClinVar as [Benign]. Clinvar id is 1232153.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-30971286-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF135	NM_032322.4	c.213C>G	p.His71Gln	missense_variant	1/5	ENST00000328381.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF135	ENST00000328381.10	c.213C>G	p.His71Gln	missense_variant	1/5	1	NM_032322.4	P1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30444 AN: 152170 Hom.: 9630 Cov.: 33

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0788

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0298

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.0860

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.152

GnomAD3 exomes AF: 0.0312 AC: 3707 AN: 118684 Hom.: 617 AF XY: 0.0277 AC XY: 1824 AN XY: 65744

Gnomad AFR exome AF: 0.687

Gnomad AMR exome AF: 0.0387

Gnomad ASJ exome AF: 0.00713

Gnomad EAS exome AF: 0.000352

Gnomad SAS exome AF: 0.0282

Gnomad FIN exome AF: 0.00620

Gnomad NFE exome AF: 0.00930

Gnomad OTH exome AF: 0.0270

GnomAD4 exome AF: 0.0248 AC: 34146 AN: 1375150 Hom.: 7520 Cov.: 31 AF XY: 0.0232 AC XY: 15750 AN XY: 678724

Gnomad4 AFR exome AF: 0.701

Gnomad4 AMR exome AF: 0.0465

Gnomad4 ASJ exome AF: 0.00727

Gnomad4 EAS exome AF: 0.0000888

Gnomad4 SAS exome AF: 0.0280

Gnomad4 FIN exome AF: 0.00596

Gnomad4 NFE exome AF: 0.00643

Gnomad4 OTH exome AF: 0.0533

GnomAD4 genome AF: 0.200 AC: 30522 AN: 152278 Hom.: 9664 Cov.: 33 AF XY: 0.194 AC XY: 14474 AN XY: 74472

Gnomad4 AFR AF: 0.675

Gnomad4 AMR AF: 0.0786

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0286

Gnomad4 FIN AF: 0.00697

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.150

Alfa AF: 0.0170 Hom.: 282

Bravo AF: 0.224

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.398 AC: 1145

ESP6500EA AF: 0.00646 AC: 39

ExAC AF: 0.0307 AC: 2135

Asia WGS AF: 0.0540 AC: 187 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	4.7
Dann	Benign	0.58
DEOGEN2	Benign	0.0047	T;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.063	T;T;T;T
MetaRNN	Benign	0.0000027	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.1	N;.;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	1.1	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.76	T;D;T;T
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.059
MutPred		0.12		Gain of ubiquitination at K74 (P = 0.0545);Gain of ubiquitination at K74 (P = 0.0545);Gain of ubiquitination at K74 (P = 0.0545);Gain of ubiquitination at K74 (P = 0.0545);
MPC		0.090
ClinPred		0.0033	T
GERP RS		3.5
Varity_R		0.047
gMVP		0.056

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7225888; hg19: chr17-29298304; COSMIC: COSV60433295; COSMIC: COSV60433295;