Genetic Variant RPS19:c.356+18G>C (chr19-41869232-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0480

Publications

5 publications found

Variant links:

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]

RPS19 Gene-Disease associations (from GenCC):

Diamond-Blackfan anemia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Diamond-Blackfan anemia 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics

RPS19 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 238214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1754 AD gene.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RPS19	NM_001022.4	MANE Select	c.356+18G>C	intron	N/A	NP_001013.1	B0ZBD0
RPS19	NM_001321485.2		c.369+18G>C	intron	N/A	NP_001308414.1
RPS19	NM_001321483.2		c.356+18G>C	intron	N/A	NP_001308412.1	B0ZBD0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RPS19	ENST00000598742.6	TSL:1 MANE Select	c.356+18G>C	intron	N/A	ENSP00000470972.1	P39019
RPS19	ENST00000593863.5	TSL:3	c.356+18G>C	intron	N/A	ENSP00000470004.1	P39019
RPS19	ENST00000600467.6	TSL:2	c.356+18G>C	intron	N/A	ENSP00000469228.2	P39019

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1755

AN:

152116

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0113

AC:

2784

AN:

245986

AF XY:

0.0114

show subpopulations

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 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.:

AF XY:

0.0156

AC XY:

11275

AN XY:

724324

show subpopulations

African (AFR)

AF:

0.00204

AC:

AN:

33338

American (AMR)

AF:

0.00229

AC:

102

AN:

44552

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

540

AN:

26076

East Asian (EAS)

AF:

0.000959

AC:

AN:

39620

South Asian (SAS)

AF:

0.00709

AC:

610

AN:

85990

European-Finnish (FIN)

AF:

0.0248

AC:

1324

AN:

53336

Middle Eastern (MID)

AF:

0.00436

AC:

AN:

4816

European-Non Finnish (NFE)

AF:

0.0179

AC:

19834

AN:

1108288

Other (OTH)

AF:

0.0140

AC:

841

AN:

60076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1129

2258

3387

4516

5645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

776

1552

2328

3104

3880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0115

AC:

1754

AN:

152234

Hom.:

Cov.:

AF XY:

0.0113

AC XY:

844

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00356

AC:

148

AN:

41568

American (AMR)

AF:

0.00353

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

AN:

3466

East Asian (EAS)

AF:

0.00232

AC:

AN:

5166

South Asian (SAS)

AF:

0.00456

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0260

AC:

276

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0168

AC:

1139

AN:

68000

Other (OTH)

AF:

0.00901

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

184

276

368

460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00477

Hom.:

Bravo

AF:

0.00914

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Diamond-Blackfan anemia 1 (3)

not provided (3)

Diamond-Blackfan anemia (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.1

(source)

DANN

Benign

0.45

PhyloP100

0.048

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over