17-30971372-A-G

Position:

• chr17-30971372-A-G

Variant summary

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

The ENST00000328381.10(RNF135):​c.299A>G​(p.His100Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,527,714 control chromosomes in the GnomAD database, including 30 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (28 hom.)
• Consequence: RNF135 ENST00000328381.10 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.202

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=0.003282249).
• BP6: Variant 17-30971372-A-G is Benign according to our data. Variant chr17-30971372-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 436547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-30971372-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 573 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF135	NM_032322.4	c.299A>G	p.His100Arg	missense_variant	1/5	ENST00000328381.10	NP_115698.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF135	ENST00000328381.10	c.299A>G	p.His100Arg	missense_variant	1/5	1	NM_032322.4	ENSP00000328340	P1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 574 AN: 152068 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00546

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00337 AC: 394 AN: 117010 Hom.: 0 AF XY: 0.00322 AC XY: 209 AN XY: 64906

Gnomad AFR exome AF: 0.000712

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.000663

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00213

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00530

Gnomad OTH exome AF: 0.00308

GnomAD4 exome AF: 0.00533 AC: 7335 AN: 1375538 Hom.: 28 Cov.: 31 AF XY: 0.00523 AC XY: 3551 AN XY: 678924

Gnomad4 AFR exome AF: 0.000937

Gnomad4 AMR exome AF: 0.000487

Gnomad4 ASJ exome AF: 0.000445

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.00602

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00377 AC: 573 AN: 152176 Hom.: 2 Cov.: 33 AF XY: 0.00362 AC XY: 269 AN XY: 74390

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.00546

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00532 Hom.: 3

Bravo AF: 0.00309

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00202 AC: 12

ExAC AF: 0.000998 AC: 61

Asia WGS AF: 0.000290 AC: 1 AN: 3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	RNF135: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.16
DANN	Benign	0.16
DEOGEN2	Benign	0.0023	T;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.28	T;T;T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.0033	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.61	N;.;N;N
REVEL	Benign	0.012
Sift	Benign	0.20	T;.;T;T
Sift4G	Benign	0.57	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.054
MVP		0.30
MPC		0.11
ClinPred		0.015	T
GERP RS		-1.2
Varity_R		0.033
gMVP		0.049

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: rs368080023; hg19: chr17-29298390;