8-56069757-G-A

Position:

chr8-56069757-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001146227.3(RPS20):c.410C>T(p.Pro137Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,551,474 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

RPS20
NM_001146227.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -1.21

Variant links:

Genes affected

RPS20 (HGNC:10405): (ribosomal protein S20) 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 40S subunit. The protein belongs to the S10P family of ribosomal proteins. It is located in the cytoplasm. This gene is co-transcribed with the small nucleolar RNA gene U54, which is located in its second intron. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Two transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Apr 2009]

RPS20 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00444898).

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS20	NM_001146227.3 linkuse as main transcript	c.410C>T	p.Pro137Leu	missense_variant	5/6		NP_001139699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
RPS20	ENST00000519807.5 linkuse as main transcript	c.410C>T	p.Pro137Leu	missense_variant	5/6	2	ENSP00000429374	P60866-2
RPS20	ENST00000618656.2 linkuse as main transcript	c.392C>T	p.Pro131Leu	missense_variant	4/5	3	ENSP00000478703
RPS20	ENST00000676461.1 linkuse as main transcript	c.*2547+786C>T		intron_variant, NMD_transcript_variant			ENSP00000504670	P60866-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000383

AC:

AN:

154076

Hom.:

AF XY:

0.000526

AC XY:

AN XY:

81760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00250

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000461

GnomAD4 exome

AF:

0.000177

AC:

247

AN:

1399242

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

175

AN XY:

690140

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00281

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000278

Gnomad4 OTH exome

AF:

0.000293

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000427

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.000820

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The RPS20 p.Pro137Leu variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs542038027) and in control databases in 59 of 149530 chromosomes (1 homozygous) at a frequency of 0.0003946 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: South Asian in 57 of 22754 chromosomes (freq: 0.002505) and Other in 2 of 4222 chromosomes (freq: 0.000474), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), or European (non-Finnish) populations. The p.Pro137 residue has limited species conservation information and three out of four computational analyses (PolyPhen-2, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.6

DANN

Benign

0.92

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.39

.;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.0044

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

0.18

N;.

REVEL

Benign

0.029

Sift

Pathogenic

0.0

D;.

Vest4

0.073

MutPred

0.16

Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);

MVP

0.043

MPC

2.0

ClinPred

0.089

GERP RS

-2.5

gMVP

0.53

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over