17-30971305-C-G

Variant names:

• chr17-30971305-C-G
• rs1475624087
• NM_032322.4:c.232C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032322.4(RNF135):​c.232C>G​(p.Leu78Val) 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. 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. L78M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RNF135 NM_032322.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20565358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF135	NM_032322.4	c.232C>G	p.Leu78Val	missense_variant	Exon 1 of 5	ENST00000328381.10	NP_115698.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF135	ENST00000328381.10	c.232C>G	p.Leu78Val	missense_variant	Exon 1 of 5	1	NM_032322.4	ENSP00000328340.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T;T;.;.
Eigen	Benign	0.067
Eigen_PC	Benign	-0.054
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.65	T;T;T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M;.;M;M
PhyloP100		1.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.8	N;N;D;N
REVEL	Benign	0.077
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.031	D;T;T;T
Polyphen		0.89	P;.;D;.
Vest4		0.12
MutPred		0.40		Loss of ubiquitination at K74 (P = 0.073);Loss of ubiquitination at K74 (P = 0.073);Loss of ubiquitination at K74 (P = 0.073);Loss of ubiquitination at K74 (P = 0.073);
MVP		0.34
MPC		0.32
ClinPred		0.96	D
GERP RS		2.4
PromoterAI		-0.10	Neutral
Varity_R		0.43
gMVP		0.11

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: rs1475624087; hg19: chr17-29298323;