17-30997303-AC-A

Variant names:

• chr17-30997303-AC-A
• rs724159977
• NM_032322.4:c.742delC

Variant summary

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

The ENST00000328381.10(RNF135):​c.742delC​(p.Leu248SerfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF135 ENST00000328381.10 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.273
• 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

ENSG00000298294 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000328381.10. 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.742delC	p.Leu248SerfsTer18	frameshift	Exon 4 of 5	NP_115698.3
	RNF135	NM_001184992.2		c.807delC	p.Ser270GlnfsTer16	frameshift	Exon 5 of 6	NP_001171921.1
	RNF135	NM_197939.2		c.579delC	p.Ser194GlnfsTer16	frameshift	Exon 3 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.742delC	p.Leu248SerfsTer18	frameshift	Exon 4 of 5	ENSP00000328340.5
	RNF135	ENST00000535306.6	TSL:1	c.807delC	p.Ser270GlnfsTer16	frameshift	Exon 5 of 6	ENSP00000440470.2
	RNF135	ENST00000324689.8	TSL:1	c.579delC	p.Ser194GlnfsTer16	frameshift	Exon 3 of 4	ENSP00000323693.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Macrocephaly, macrosomia, facial dysmorphism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.27
Mutation Taster		=30/170	disease causing

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

Other links and lift over

dbSNP: rs724159977; hg19: chr17-29324321;