18-49490871-C-A

Position:

• chr18-49490871-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 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. 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

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL17	NM_001035006.5	c.138G>T	p.Lys46Asn	missense_variant	4/7	ENST00000580261.6	NP_001030178.1
RPL17-C18orf32	NM_001199356.2	c.24G>T	p.Lys8Asn	missense_variant	3/7		NP_001186285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL17	ENST00000580261.6	c.138G>T	p.Lys46Asn	missense_variant	4/7	1	NM_001035006.5	ENSP00000462385	P1
	ENST00000581232.1	n.480-905C>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249344 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135276

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2024

The c.138G>T (p.K46N) alteration is located in exon 4 (coding exon 3) of the RPL17 gene. This alteration results from a G to T substitution at nucleotide position 138, causing the lysine (K) at amino acid position 46 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;.;T;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;.;.;.;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	.;.;N;N;N;N;.;N;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PROVEAN	Benign	-2.2	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.071
Sift	Uncertain	0.0090	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.053	T;D;T;T;T;T;T;T;T;T;T;T;T;.;.;.;D
Polyphen		0.075	.;.;B;B;B;B;.;B;.;.;.;.;.;.;.;.;.
Vest4		0.73
MutPred		0.48		Loss of phosphorylation at T45 (P = 0.0837);.;Loss of phosphorylation at T45 (P = 0.0837);Loss of phosphorylation at T45 (P = 0.0837);Loss of phosphorylation at T45 (P = 0.0837);Loss of phosphorylation at T45 (P = 0.0837);.;Loss of phosphorylation at T45 (P = 0.0837);.;Loss of phosphorylation at T45 (P = 0.0837);Loss of phosphorylation at T45 (P = 0.0837);Loss of phosphorylation at T45 (P = 0.0837);Loss of phosphorylation at T45 (P = 0.0837);Loss of phosphorylation at T45 (P = 0.0837);Loss of phosphorylation at T45 (P = 0.0837);Loss of phosphorylation at T45 (P = 0.0837);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1230057203; hg19: chr18-47017241;