18-49490871-C-A

Variant names:

• chr18-49490871-C-A
• rs1230057203
• NM_001035006.5:c.138G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001035006.5(RPL17):​c.138G>T​(p.Lys46Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RPL17 NM_001035006.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.992
• 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:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26435888).

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.138G>T	p.Lys46Asn	missense	Exon 4 of 7	NP_001030178.1	P18621-1
	RPL17-C18orf32	NM_001199355.1		c.138G>T	p.Lys46Asn	missense	Exon 3 of 7	NP_001186284.1	A0A0A6YYL6
	RPL17-C18orf32	NM_001199356.2		c.24G>T	p.Lys8Asn	missense	Exon 3 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.138G>T	p.Lys46Asn	missense	Exon 4 of 7	ENSP00000462385.1	P18621-1
	RPL17-C18orf32	ENST00000584895.5	TSL:3	c.138G>T	p.Lys46Asn	missense	Exon 3 of 7	ENSP00000463379.1
	RPL17	ENST00000579408.5	TSL:1	c.138G>T	p.Lys46Asn	missense	Exon 3 of 6	ENSP00000463842.1	P18621-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249344 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461462 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727012

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111890

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	N
PhyloP100		0.99
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.071
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.053	T
Polyphen		0.075	B
Vest4		0.73
MutPred		0.48		Loss of phosphorylation at T45 (P = 0.0837)
MVP		0.51
MPC		2.2
ClinPred		0.78	D
GERP RS		1.8
Varity_R		0.21
gMVP		0.62
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1230057203; hg19: chr18-47017241;