17-30971395-T-C

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.322T>C(p.Ser108Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 1,522,404 control chromosomes in the GnomAD database, including 17,157 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 (9582 hom., cov: 33)
  • Exomes 𝑓: 0.025 (7575 hom.)
• Consequence: RNF135 NM_032322.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.76

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=5.844231E-6).
• BP6: Variant 17-30971395-T-C is Benign according to our data. Variant chr17-30971395-T-C is described in ClinVar as [Benign]. Clinvar id is 1296606.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF135	NM_032322.4	c.322T>C	p.Ser108Pro	missense_variant	1/5	ENST00000328381.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF135	ENST00000328381.10	c.322T>C	p.Ser108Pro	missense_variant	1/5	1	NM_032322.4	P1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30338 AN: 152032 Hom.: 9551 Cov.: 33

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0777

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0300

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.153

GnomAD3 exomes AF: 0.0339 AC: 3896 AN: 114962 Hom.: 679 AF XY: 0.0303 AC XY: 1941 AN XY: 63954

Gnomad AFR exome AF: 0.694

Gnomad AMR exome AF: 0.0391

Gnomad ASJ exome AF: 0.00705

Gnomad EAS exome AF: 0.000365

Gnomad SAS exome AF: 0.0288

Gnomad FIN exome AF: 0.00637

Gnomad NFE exome AF: 0.00936

Gnomad OTH exome AF: 0.0262

GnomAD4 exome AF: 0.0250 AC: 34240 AN: 1370264 Hom.: 7575 Cov.: 31 AF XY: 0.0233 AC XY: 15787 AN XY: 676426

Gnomad4 AFR exome AF: 0.701

Gnomad4 AMR exome AF: 0.0461

Gnomad4 ASJ exome AF: 0.00723

Gnomad4 EAS exome AF: 0.0000893

Gnomad4 SAS exome AF: 0.0282

Gnomad4 FIN exome AF: 0.00600

Gnomad4 NFE exome AF: 0.00637

Gnomad4 OTH exome AF: 0.0528

GnomAD4 genome AF: 0.200 AC: 30414 AN: 152140 Hom.: 9582 Cov.: 33 AF XY: 0.193 AC XY: 14382 AN XY: 74384

Gnomad4 AFR AF: 0.673

Gnomad4 AMR AF: 0.0775

Gnomad4 ASJ AF: 0.00923

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.00697

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.151

Alfa AF: 0.0816 Hom.: 1208

Bravo AF: 0.224

ESP6500AA AF: 0.378 AC: 1011

ESP6500EA AF: 0.00561 AC: 30

ExAC AF: 0.0305 AC: 1412

Asia WGS AF: 0.0530 AC: 186 AN: 3470

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	0.051
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	0.88
Dann	Benign	0.31
DEOGEN2	Benign	0.011	T;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00037	N
LIST_S2	Benign	0.27	T;T;T;T
MetaRNN	Benign	0.0000058	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.3	N;.;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	1.1	N;.;N;N
REVEL	Benign	0.038
Sift	Benign	0.34	T;.;T;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.088
MPC		0.11
ClinPred		0.0069	T
GERP RS		1.7
Varity_R		0.057
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7211440; hg19: chr17-29298413; COSMIC: COSV60433303; COSMIC: COSV60433303;