chr17-30971150-G-A

Variant names:

• chr17-30971150-G-A
• rs1487820448
• NM_032322.4:c.77G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032322.4(RNF135):​c.77G>A​(p.Gly26Glu) 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. 15/22 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. G26A) 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: -0.0460
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030392647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF135	NM_032322.4	c.77G>A	p.Gly26Glu	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.77G>A	p.Gly26Glu	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

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.83
DEOGEN2	Benign	0.0025	T;T;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.62	T;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.030	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.30	N;.;N;N
PhyloP100		-0.046
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	1.1	N;.;N;N
REVEL	Benign	0.070
Sift	Benign	0.93	T;.;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0030	B;.;B;.
Vest4		0.051
MutPred		0.50		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.25
MPC		0.12
ClinPred		0.087	T
GERP RS		-3.1
PromoterAI		0.035	Neutral
Varity_R		0.036
gMVP		0.19

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: rs1487820448; hg19: chr17-29298168;