NM_001022.4:c.356+18G>C

Variant names:

• chr19-41869232-G-C
• rs61762294
• NM_001022.4:c.356+18G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001022.4(RPS19):​c.356+18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,608,326 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 32)
  • Exomes 𝑓: 0.016 (216 hom.)
• Consequence: RPS19 NM_001022.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0480

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-41869232-G-C is Benign according to our data. Variant chr19-41869232-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 238214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41869232-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0115 (1754/152234) while in subpopulation NFE AF= 0.0168 (1139/68000). AF 95% confidence interval is 0.0159. There are 18 homozygotes in gnomad4. There are 844 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1754 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS19	NM_001022.4	c.356+18G>C		intron_variant	Intron 4 of 5	ENST00000598742.6	NP_001013.1
RPS19	NM_001321485.2	c.369+18G>C		intron_variant	Intron 4 of 5		NP_001308414.1
RPS19	NM_001321483.2	c.356+18G>C		intron_variant	Intron 4 of 5		NP_001308412.1
RPS19	NM_001321484.2	c.356+18G>C		intron_variant	Intron 4 of 5		NP_001308413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS19	ENST00000598742.6	c.356+18G>C		intron_variant	Intron 4 of 5	1	NM_001022.4	ENSP00000470972.1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1755 AN: 152116 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0260

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.00911

GnomAD3 exomes AF: 0.0113 AC: 2784 AN: 245986 Hom.: 28 AF XY: 0.0114 AC XY: 1527 AN XY: 133814

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.00181

Gnomad SAS exome AF: 0.00742

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0161 AC: 23378 AN: 1456092 Hom.: 216 Cov.: 31 AF XY: 0.0156 AC XY: 11275 AN XY: 724324

Gnomad4 AFR exome AF: 0.00204

Gnomad4 AMR exome AF: 0.00229

Gnomad4 ASJ exome AF: 0.0207

Gnomad4 EAS exome AF: 0.000959

Gnomad4 SAS exome AF: 0.00709

Gnomad4 FIN exome AF: 0.0248

Gnomad4 NFE exome AF: 0.0179

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.0115 AC: 1754 AN: 152234 Hom.: 18 Cov.: 32 AF XY: 0.0113 AC XY: 844 AN XY: 74416

Gnomad4 AFR AF: 0.00356

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0260

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.00901

Alfa AF: 0.00708 Hom.: 2

Bravo AF: 0.00914

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia 1 Benign:3

Aug 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous c.356+18G>C variant in RPS19 has been identified in an individual with Diamond-Blackfan anaemia (PMID: 10590074), but has also been identified in >2% of European (Finnish) chromosomes and 14 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Diamond-Blackfan anaemia. -

Dec 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Dec 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10590074, 27535533) -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RPS19: BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Diamond-Blackfan anemia Benign:2

May 20, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.1
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61762294; hg19: chr19-42373302;