Genetic Variant RPS19:c.-1+36C>T (chr19-41860325-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001022.4(RPS19):c.-1+36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 153,960 control chromosomes in the GnomAD database, including 16,266 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.44 ( 15954 hom., cov: 34)

Exomes 𝑓: 0.56 ( 312 hom. )

Consequence

RPS19
NM_001022.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.15

Publications

6 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:

ENSG00000306611 (HGNC:):

ENSG00000306611 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RPS19	NM_001022.4 link	c.-1+36C>T	intron_variant	Intron 1 of 5	ENST00000598742.6	NP_001013.1	P39019B0ZBD0
RPS19	NM_001321484.2 link	c.-121C>T	5_prime_UTR_variant	Exon 1 of 6		NP_001308413.1	P39019B0ZBD0
RPS19	NM_001321485.2 link	c.-1+36C>T	intron_variant	Intron 1 of 5		NP_001308414.1
RPS19	NM_001321483.2 link	c.-170C>T	upstream_gene_variant			NP_001308412.1	P39019B0ZBD0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS19	ENST00000598742.6 link	c.-1+36C>T		intron_variant	Intron 1 of 5	1	NM_001022.4	ENSP00000470972.1		P39019

Frequencies

GnomAD3 genomes

AF:

0.438

AC:

66574

AN:

151966

Hom.:

15959

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.564

Gnomad AMR

AF:

0.500

Gnomad ASJ

AF:

0.616

Gnomad EAS

AF:

0.460

Gnomad SAS

AF:

0.573

Gnomad FIN

AF:

0.516

Gnomad MID

AF:

0.685

Gnomad NFE

AF:

0.513

Gnomad OTH

AF:

0.492

GnomAD4 exome

AF:

0.557

AC:

1047

AN:

1880

Hom.:

312

Cov.:

AF XY:

0.560

AC XY:

594

AN XY:

1060

show subpopulations

African (AFR)

AF:

0.274

AC:

AN:

American (AMR)

AF:

0.625

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.622

AC:

AN:

East Asian (EAS)

AF:

0.538

AC:

AN:

South Asian (SAS)

AF:

0.685

AC:

AN:

European-Finnish (FIN)

AF:

0.548

AC:

183

AN:

334

Middle Eastern (MID)

AF:

0.800

AC:

AN:

European-Non Finnish (NFE)

AF:

0.558

AC:

638

AN:

1144

Other (OTH)

AF:

0.610

AC:

AN:

100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.438

AC:

66578

AN:

152080

Hom.:

15954

Cov.:

AF XY:

0.443

AC XY:

32912

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.231

AC:

9599

AN:

41504

American (AMR)

AF:

0.500

AC:

7642

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.616

AC:

2137

AN:

3470

East Asian (EAS)

AF:

0.460

AC:

2378

AN:

5174

South Asian (SAS)

AF:

0.571

AC:

2759

AN:

4828

European-Finnish (FIN)

AF:

0.516

AC:

5460

AN:

10576

Middle Eastern (MID)

AF:

0.685

AC:

200

AN:

292

European-Non Finnish (NFE)

AF:

0.513

AC:

34862

AN:

67932

Other (OTH)

AF:

0.487

AC:

1028

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1851

3702

5553

7404

9255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

616

1232

1848

2464

3080

<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:

0.464

Hom.:

2100

Bravo

AF:

0.424

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

4.4

(source)

PhyloP100

-1.1

PromoterAI

0.0074

Neutral

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over