NM_001022.4:c.380G>A

Variant names:

• chr19-41869722-G-A
• rs786200936
• NM_001022.4:c.380G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001022.4(RPS19):​c.380G>A​(p.Gly127Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G127R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS19 NM_001022.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.51
• Publications: 8 publications found

Genes affected

RPS19 (HGNC:10402): (ribosomal protein S19) 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 S19E family of ribosomal proteins. It is located in the cytoplasm. Mutations in this gene cause Diamond-Blackfan anemia (DBA), a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors, in a subset of patients. This suggests a possible extra-ribosomal function for this gene in erythropoietic differentiation and proliferation, in addition to its ribosomal function. Higher expression levels of this gene in some primary colon carcinomas compared to matched normal colon tissues has been observed. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

MIR6797 (HGNC:50169): (microRNA 6797) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a chain Small ribosomal subunit protein eS19 (size 143) in uniprot entity RS19_HUMAN there are 24 pathogenic changes around while only 2 benign (92%) in NM_001022.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 19-41869722-G-A is Pathogenic according to our data. Variant chr19-41869722-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 6320.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001022.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS19	NM_001022.4	MANE Select	c.380G>A	p.Gly127Glu	missense	Exon 5 of 6	NP_001013.1
	RPS19	NM_001321483.2		c.380G>A	p.Gly127Glu	missense	Exon 5 of 6	NP_001308412.1
	RPS19	NM_001321484.2		c.380G>A	p.Gly127Glu	missense	Exon 5 of 6	NP_001308413.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS19	ENST00000598742.6	TSL:1 MANE Select	c.380G>A	p.Gly127Glu	missense	Exon 5 of 6	ENSP00000470972.1
	RPS19	ENST00000593863.5	TSL:3	c.380G>A	p.Gly127Glu	missense	Exon 5 of 6	ENSP00000470004.1
	RPS19	ENST00000600467.6	TSL:2	c.380G>A	p.Gly127Glu	missense	Exon 5 of 6	ENSP00000469228.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia 1 Pathogenic:1

Jul 15, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Diamond-Blackfan anemia Pathogenic:1

Jan 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individuals with clinical features of Diamond-Blackfan anemia (PMID: 10590074, 31574871; Invitae). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 127 of the RPS19 protein (p.Gly127Glu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 6320). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RPS19 function (PMID: 12586610, 17517689, 18768533). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.5
PrimateAI	Uncertain	0.77	T
REVEL	Pathogenic	0.75
Sift4G	Uncertain	0.034	D
Polyphen		0.99	D
Vest4		0.98
MutPred		0.98		Loss of MoRF binding (P = 0.0171)
MVP		0.97
MPC		2.3
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.97
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.0		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: rs786200936; hg19: chr19-42373792; COSMIC: COSV108786786; COSMIC: COSV108786786;