19-41860773-A-C

Variant names:

• chr19-41860773-A-C
• NM_001022.4:c.1-2A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001022.4(RPS19):​c.1-2A>C variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS19 NM_001022.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.08

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.16210045 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.9, offset of -33, new splice context is: ttggcagtcgtctctgccAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-41860773-A-C is Pathogenic according to our data. Variant chr19-41860773-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 3766828.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS19	NM_001022.4	c.1-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 5	ENST00000598742.6	NP_001013.1
RPS19	NM_001321485.2	c.1-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 5		NP_001308414.1
RPS19	NM_001321483.2	c.1-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 5		NP_001308412.1
RPS19	NM_001321484.2	c.1-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 5		NP_001308413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS19	ENST00000598742.6	c.1-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 5	1	NM_001022.4	ENSP00000470972.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia 1 Pathogenic:1

Sep 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RPS19 c.1-2A>C variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this canonical splice site (c.1-2A>G, c.1-2A>T) have been reported in individuals with Diamond-Blackfan anemia and are considered disease causing (Boria 2010, Wan 2016). This variant disrupts the canonical splice acceptor site of intron 1, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Boria I et al. The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update. Hum Mutat. 2010 Dec;31(12):1269-79. PMID: 20960466. Wan Y et al. Clinical features, mutations and treatment of 104 patients of Diamond-Blackfan anemia in China: a single-center retrospective study. Int J Hematol. 2016 Oct;104(4):430-9. PMID: 27329125. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	34
DANN	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.55		Position offset: 12
DS_AL_spliceai		0.99		Position offset: 2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-42364843;