chr17-30971417-G-A

Variant names:

• chr17-30971417-G-A
• rs111902263
• NM_032322.4:c.344G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:6
• Conservation: PhyloP100: -1.39
• Publications: 14 publications found

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]

RNF135 Gene-Disease associations (from GenCC):

• overgrowth-macrocephaly-facial dysmorphism syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• overgrowth syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264456 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 436548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2182 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032322.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF135	NM_032322.4	MANE Select	c.344G>A	p.Arg115Lys	missense	Exon 1 of 5	NP_115698.3
	RNF135	NM_001184992.2		c.344G>A	p.Arg115Lys	missense	Exon 1 of 6	NP_001171921.1
	RNF135	NM_197939.2		c.344G>A	p.Arg115Lys	missense	Exon 1 of 4	NP_922921.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF135	ENST00000328381.10	TSL:1 MANE Select	c.344G>A	p.Arg115Lys	missense	Exon 1 of 5	ENSP00000328340.5
	RNF135	ENST00000535306.6	TSL:1	c.344G>A	p.Arg115Lys	missense	Exon 1 of 6	ENSP00000440470.2
	RNF135	ENST00000324689.8	TSL:1	c.344G>A	p.Arg115Lys	missense	Exon 1 of 4	ENSP00000323693.4

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

GnomAD2 exomes AF: 0.0124 AC: 1373 AN: 110488 AF XY: 0.0119

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 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

African (AFR) AF: 0.00389 AC: 109 AN: 28052

American (AMR) AF: 0.0132 AC: 450 AN: 33974

Ashkenazi Jewish (ASJ) AF: 0.00397 AC: 97 AN: 24440

East Asian (EAS) AF: 0.0000302 AC: 1 AN: 33140

South Asian (SAS) AF: 0.000542 AC: 42 AN: 77490

European-Finnish (FIN) AF: 0.0264 AC: 925 AN: 35068

Middle Eastern (MID) AF: 0.00300 AC: 12 AN: 4000

European-Non Finnish (NFE) AF: 0.0227 AC: 24325 AN: 1071488

Other (OTH) AF: 0.0167 AC: 948 AN: 56812

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

African (AFR) AF: 0.00476 AC: 198 AN: 41572

American (AMR) AF: 0.0177 AC: 271 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0257 AC: 273 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0203 AC: 1382 AN: 68020

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.0140 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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26368817)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Mar 23, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 28, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNF135-related disorder Benign:1

Apr 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0072	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.077
Sift	Benign	0.48	T
Sift4G	Benign	0.37	T
Polyphen		0.023	B
Vest4		0.039
MPC		0.095
ClinPred		0.0026	T
GERP RS		-0.71
PromoterAI		-0.22	Neutral
Varity_R		0.084
gMVP		0.16
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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