8-56069749-A-G

Variant names:

• chr8-56069749-A-G
• NM_001146227.3:c.418T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001146227.3(RPS20):​c.418T>C​(p.Cys140Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C140S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RPS20 NM_001146227.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.445
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia

  Inheritance: AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Orphanet, Ambry Genetics
• familial colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial colorectal cancer type X

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Lynch syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07165781).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146227.3. 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
	RPS20	NM_001146227.3		c.418T>C	p.Cys140Arg	missense	Exon 5 of 6	NP_001139699.1	P60866-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS20	ENST00000519807.5	TSL:2	c.418T>C	p.Cys140Arg	missense	Exon 5 of 6	ENSP00000429374.1	P60866-2
	RPS20	ENST00000618656.2	TSL:3	c.400T>C	p.Cys134Arg	missense	Exon 4 of 5	ENSP00000478703.2	A0A7P0S5H5
	RPS20	ENST00000676918.1		n.*3341T>C		non_coding_transcript_exon	Exon 4 of 5	ENSP00000503327.1	P60866-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399352 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690182

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078928

Other (OTH) AF: 0.00 AC: 0 AN: 58000

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	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	2.2
DANN	Benign	0.88
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.45
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.079
Sift	Pathogenic	0.0	D
Vest4		0.17
MutPred		0.14		Gain of solvent accessibility (P = 0.0328)
MVP		0.043
MPC		2.3
ClinPred		0.20	T
GERP RS		1.9
gMVP		0.65
Mutation Taster		=87/13	polymorphism

Splicing

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

Other links and lift over

hg19: chr8-56982308;