Genetic Variant NM_001018.5:c.63C>T (chr19-1438866-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001018.5(RPS15):c.63C>T(p.Asp21Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,590,574 control chromosomes in the GnomAD database, including 2,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 258 hom., cov: 32)

Exomes 𝑓: 0.052 ( 2192 hom. )

Consequence

RPS15
NM_001018.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.251

Publications

13 publications found

Variant links:

Genes affected

RPS15 (HGNC:10388): (ribosomal protein S15) 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 S19P family of ribosomal proteins. It is located in the cytoplasm. This gene has been found to be activated in various tumors, such as insulinomas, esophageal cancers, and colon cancers. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

RPS15 Gene-Disease associations (from GenCC):

Diamond-Blackfan anemia
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

RPS15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 19-1438866-C-T is Benign according to our data. Variant chr19-1438866-C-T is described in ClinVar as Benign. ClinVar VariationId is 440243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.251 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0633 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS15	NM_001018.5	MANE Select	c.63C>T	p.Asp21Asp	synonymous	Exon 2 of 4	NP_001009.1	P62841
	RPS15	NM_001308226.2		c.84C>T	p.Asp28Asp	synonymous	Exon 2 of 4	NP_001295155.1	K7ELC2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPS15	ENST00000592588.7	TSL:1 MANE Select	c.63C>T	p.Asp21Asp	synonymous	Exon 2 of 4	ENSP00000467466.3	P62841
RPS15	ENST00000592623.5	TSL:1	c.-19C>T		5_prime_UTR	Exon 1 of 3	ENSP00000474433.2	A0A0B4J2B4
RPS15	ENST00000593052.5	TSL:2	c.84C>T	p.Asp28Asp	synonymous	Exon 2 of 4	ENSP00000466010.1	K7ELC2

Frequencies

GnomAD3 genomes

AF:

0.0538

AC:

8190

AN:

152170

Hom.:

254

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0483

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0428

Gnomad ASJ

AF:

0.0853

Gnomad EAS

AF:

0.0358

Gnomad SAS

AF:

0.0704

Gnomad FIN

AF:

0.0782

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0539

Gnomad OTH

AF:

0.0735

GnomAD2 exomes

AF:

0.0526

AC:

11189

AN:

212584

AF XY:

0.0551

show subpopulations

Gnomad AFR exome

AF:

0.0464

Gnomad AMR exome

AF:

0.0230

Gnomad ASJ exome

AF:

0.0837

Gnomad EAS exome

AF:

0.0387

Gnomad FIN exome

AF:

0.0779

Gnomad NFE exome

AF:

0.0510

Gnomad OTH exome

AF:

0.0470

GnomAD4 exome

AF:

0.0517

AC:

74306

AN:

1438288

Hom.:

2192

Cov.:

AF XY:

0.0530

AC XY:

37822

AN XY:

713588

show subpopulations

African (AFR)

AF:

0.0455

AC:

1493

AN:

32828

American (AMR)

AF:

0.0246

AC:

1051

AN:

42760

Ashkenazi Jewish (ASJ)

AF:

0.0848

AC:

2180

AN:

25720

East Asian (EAS)

AF:

0.0287

AC:

1106

AN:

38506

South Asian (SAS)

AF:

0.0767

AC:

6392

AN:

83294

European-Finnish (FIN)

AF:

0.0752

AC:

3805

AN:

50592

Middle Eastern (MID)

AF:

0.0858

AC:

358

AN:

4172

European-Non Finnish (NFE)

AF:

0.0497

AC:

54725

AN:

1101128

Other (OTH)

AF:

0.0539

AC:

3196

AN:

59288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

3957

7915

11872

15830

19787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2044

4088

6132

8176

10220

<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:

0.0539

AC:

8212

AN:

152286

Hom.:

258

Cov.:

AF XY:

0.0558

AC XY:

4152

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0487

AC:

2024

AN:

41552

American (AMR)

AF:

0.0427

AC:

653

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0853

AC:

296

AN:

3470

East Asian (EAS)

AF:

0.0357

AC:

185

AN:

5178

South Asian (SAS)

AF:

0.0694

AC:

335

AN:

4828

European-Finnish (FIN)

AF:

0.0782

AC:

829

AN:

10604

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0539

AC:

3665

AN:

68028

Other (OTH)

AF:

0.0761

AC:

161

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

392

784

1176

1568

1960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<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:

0.0532

Hom.:

204

Bravo

AF:

0.0495

Asia WGS

AF:

0.0820

AC:

284

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

0.25

PromoterAI

-0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over