18-49489413-CG-C

Variant names:

• chr18-49489413-CG-C
• NM_001035006.5:c.452delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001035006.5(RPL17):​c.452delC​(p.Thr151ArgfsTer25) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPL17 NM_001035006.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.43
• Publications: 0 publications found

Genes affected

RPL17 (HGNC:10307): (ribosomal protein L17) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L22P family of ribosomal proteins. It is located in the cytoplasm. This gene has been referred to as rpL23 because the encoded protein shares amino acid identity with ribosomal protein L23 from Halobacterium marismortui; however, its official symbol is RPL17. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring downstream C18orf32 (chromosome 18 open reading frame 32) gene. [provided by RefSeq, Dec 2010]

RPL17-C18orf32 (HGNC:44661): (RPL17-C18orf32 readthrough) This locus represents naturally occurring read-through transcription between the neighboring RPL17 (ribosomal protein L17) and C18orf32 (chromosome 18 open reading frame 32) genes. Alternative splicing results in multiple transcript variants. The encoded isoforms share sequence identity with the RPL17 protein, but they include frameshifted C-terminal regions derived from the downstream gene exons. [provided by RefSeq, Dec 2010]

ENSG00000265496 (HGNC:):

SNORD58C (HGNC:33613): (small nucleolar RNA, C/D box 58C)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-49489413-CG-C is Pathogenic according to our data. Variant chr18-49489413-CG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3233357.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035006.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL17	NM_001035006.5	MANE Select	c.452delC	p.Thr151ArgfsTer25	frameshift	Exon 6 of 7	NP_001030178.1	P18621-1
	RPL17-C18orf32	NM_001199355.1		c.452delC	p.Thr151ArgfsTer20	frameshift	Exon 5 of 7	NP_001186284.1	A0A0A6YYL6
	RPL17-C18orf32	NM_001199356.2		c.338delC	p.Thr113ArgfsTer20	frameshift	Exon 5 of 7	NP_001186285.1	A0A0A0MRF8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL17	ENST00000580261.6	TSL:1 MANE Select	c.452delC	p.Thr151ArgfsTer25	frameshift	Exon 6 of 7	ENSP00000462385.1	P18621-1
	RPL17-C18orf32	ENST00000584895.5	TSL:3	c.452delC	p.Thr151ArgfsTer20	frameshift	Exon 5 of 7	ENSP00000463379.1
	RPL17	ENST00000579408.5	TSL:1	c.452delC	p.Thr151ArgfsTer25	frameshift	Exon 5 of 6	ENSP00000463842.1	P18621-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Macrocytic anemia;C0004352:Autism;C0015934:Fetal growth restriction;C0030312:Pancytopenia;C0235991:Small for gestational age;C0239676:High forehead;C0678230:Epicanthus;C1263846:Attention deficit hyperactivity disorder;C1835884:Triangular face;C1867873:Failure to thrive in infancy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4

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

hg19: chr18-47015783;