17-30971365-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032322.4(RNF135):c.292C>G(p.Pro98Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,529,442 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: RNF135 NM_032322.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.528

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036907792).
• BP6: Variant 17-30971365-C-G is Benign according to our data. Variant chr17-30971365-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 781275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 552 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF135	NM_032322.4	c.292C>G	p.Pro98Ala	missense_variant	1/5	ENST00000328381.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF135	ENST00000328381.10	c.292C>G	p.Pro98Ala	missense_variant	1/5	1	NM_032322.4	P1

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 552 AN: 152204 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000504 AC: 61 AN: 121002 Hom.: 0 AF XY: 0.000374 AC XY: 25 AN XY: 66880

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.000720

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000464

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000679

Gnomad OTH exome AF: 0.000269

GnomAD4 exome AF: 0.000341 AC: 469 AN: 1377130 Hom.: 3 Cov.: 31 AF XY: 0.000287 AC XY: 195 AN XY: 679744

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.000800

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000383

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000419

Gnomad4 OTH exome AF: 0.000733

GnomAD4 genome AF: 0.00363 AC: 553 AN: 152312 Hom.: 3 Cov.: 33 AF XY: 0.00373 AC XY: 278 AN XY: 74466

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00174 Hom.: 1

Bravo AF: 0.00382

ESP6500AA AF: 0.000994 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000169 AC: 11

Asia WGS AF: 0.000870 AC: 3 AN: 3464

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 27, 2019

- -

RNF135-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 2019

This variant is classified as likely 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	0.053
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	0.056
Dann	Benign	0.53
DEOGEN2	Benign	0.0073	T;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.39	T;T;T;T
MetaRNN	Benign	0.0037	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.4	N;.;D;D
REVEL	Benign	0.028
Sift	Benign	0.61	T;.;D;D
Sift4G	Benign	0.66	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.062
MVP		0.26
MPC		0.087
ClinPred		0.012	T
GERP RS		-0.20
Varity_R		0.027
gMVP		0.050

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: rs376823094; hg19: chr17-29298383;