19-41861204-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_001022.4(RPS19):c.164C>T(p.Thr55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,613,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T55T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

RPS19
NM_001022.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 2.56

Publications

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

RPS19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001022.4

BP4

Computational evidence support a benign effect (MetaRNN=0.29573745).

BS2

High AC in GnomAd4 at 55 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	HGVSp	Effect	Exon Rank	Protein
RPS19	NM_001022.4	MANE Select	c.164C>T	p.Thr55Met	missense	Exon 3 of 6	NP_001013.1
RPS19	NM_001321485.2		c.164C>T	p.Thr55Met	missense	Exon 3 of 6	NP_001308414.1
RPS19	NM_001321483.2		c.164C>T	p.Thr55Met	missense	Exon 3 of 6	NP_001308412.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPS19	ENST00000598742.6	TSL:1 MANE Select	c.164C>T	p.Thr55Met	missense	Exon 3 of 6	ENSP00000470972.1
RPS19	ENST00000221975.6	TSL:3	c.-59C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	ENSP00000221975.2
RPS19	ENST00000593863.5	TSL:3	c.164C>T	p.Thr55Met	missense	Exon 3 of 6	ENSP00000470004.1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000247

AC:

AN:

251298

AF XY:

0.000228

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000927

Gnomad NFE exome

AF:

0.000484

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000504

AC:

737

AN:

1460934

Hom.:

Cov.:

AF XY:

0.000469

AC XY:

341

AN XY:

726842

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33466

American (AMR)

AF:

0.0000894

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000624

AC:

693

AN:

1111190

Other (OTH)

AF:

0.000414

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000361

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000676

AC:

AN:

68042

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000548

Hom.:

Bravo

AF:

0.000332

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Diamond-Blackfan anemia 1

Uncertain:2Benign:1

Apr 06, 2020

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Mar 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 10, 2024

Undiagnosed Diseases Network, NIH

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Jul 07, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hepatoblastoma

Uncertain:1

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

Diamond-Blackfan anemia

Uncertain:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 55 of the RPS19 protein (p.Thr55Met). This variant is present in population databases (rs147508369, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Diamond-Blackfan anemia (PMID: 12586610). ClinVar contains an entry for this variant (Variation ID: 242753). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect RPS19 function (PMID: 12586610). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.1

PhyloP100

2.6

PrimateAI

Uncertain

0.76

Sift4G

Benign

0.062

Polyphen

0.91

Vest4

0.65

MVP

0.62

MPC

1.2

ClinPred

0.083

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.43

gMVP

0.55

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over