17-30971372-A-C

Position:

• chr17-30971372-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032322.4(RNF135):​c.299A>C​(p.His100Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H100R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RNF135 NM_032322.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03390518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF135	NM_032322.4	c.299A>C	p.His100Pro	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>C	p.His100Pro	missense_variant	1/5	1	NM_032322.4	ENSP00000328340.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.30
DANN	Benign	0.14
DEOGEN2	Benign	0.0018	T;T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.22	T;T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.034	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;.;N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	1.1	N;.;N;N
REVEL	Benign	0.059
Sift	Benign	0.45	T;.;T;T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.092
MutPred		0.29		Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);
MVP		0.23
MPC		0.14
ClinPred		0.11	T
GERP RS		-1.2
Varity_R		0.049
gMVP		0.13

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: rs368080023; hg19: chr17-29298390;