18-49488532-A-G

Position:

• chr18-49488532-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001035006.5(RPL17):​c.542T>C​(p.Met181Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,556,396 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: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: RPL17 NM_001035006.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.60

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34254023).
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL17	NM_001035006.5	c.542T>C	p.Met181Thr	missense_variant	7/7	ENST00000580261.6	NP_001030178.1
RPL17-C18orf32	NM_001199356.2	c.393+827T>C		intron_variant			NP_001186285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL17	ENST00000580261.6	c.542T>C	p.Met181Thr	missense_variant	7/7	1	NM_001035006.5	ENSP00000462385	P1
	ENST00000581232.1	n.479+715A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000205 AC: 51 AN: 248996 Hom.: 0 AF XY: 0.000200 AC XY: 27 AN XY: 135092

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.000274

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000211 AC: 296 AN: 1404086 Hom.: 0 Cov.: 24 AF XY: 0.000201 AC XY: 141 AN XY: 702004

Gnomad4 AFR exome AF: 0.0000931

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.000197

Gnomad4 OTH exome AF: 0.000462

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74478

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000278 AC: 1

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.000190 AC: 23

EpiCase AF: 0.000109

EpiControl AF: 0.000237

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

Jun 01, 2023

The c.542T>C (p.M181T) alteration is located in exon 7 (coding exon 6) of the RPL17 gene. This alteration results from a T to C substitution at nucleotide position 542, causing the methionine (M) at amino acid position 181 to be replaced by a threonine (T). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.062	T;T;T;T;.;T;.
Eigen	Benign	0.083
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.61	.;.;.;.;T;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.34	T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M;M;M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.099	T;T;T;T;T;T;T
Polyphen		0.0020	B;B;B;B;.;B;.
Vest4		0.79
MVP		0.53
ClinPred		0.095	T
GERP RS		5.1
Varity_R		0.27
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs200376678; hg19: chr18-47014902; COSMIC: COSV59087486; COSMIC: COSV59087486;