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GeneBe

15-82540427-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001021.6(RPS17):c.2T>G(p.Met1?) variant causes a start lost, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

RPS17
NM_001021.6 start_lost, splice_region

Scores

5
4
2
Splicing: ADA: 0.009343
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.19
Variant links:
Genes affected
RPS17 (HGNC:10397): (ribosomal protein S17) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of four 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 S17E family of ribosomal proteins and is located in the cytoplasm. Mutations in this gene cause Diamond-Blackfan anemia 4. Alternative splicing of this gene results in multiple transcript variants. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Apr 2014]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-82540427-A-C is Pathogenic according to our data. Variant chr15-82540427-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 12999.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPS17NM_001021.6 linkuse as main transcriptc.2T>G p.Met1? start_lost, splice_region_variant 1/5 ENST00000647841.1
RPS17NR_111943.2 linkuse as main transcriptn.31T>G non_coding_transcript_exon_variant 1/4
RPS17NR_111944.3 linkuse as main transcriptn.31T>G splice_region_variant, non_coding_transcript_exon_variant 1/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPS17ENST00000647841.1 linkuse as main transcriptc.2T>G p.Met1? start_lost, splice_region_variant 1/5 NM_001021.6 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Diamond-Blackfan anemia 4 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2007- -
Diamond-Blackfan anemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 14, 2015The p.M1? pathogenic mutation (also known as c.2T>G), located in coding exon 1 of the RPS17 gene, results from a T to G substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. This mutation was found de novo in a patient with typical anemia, dysmorphic facial features, and short stature and was not observed in 71 healthy controls (Cmejla et al 2007. Hum Mutat.28(12):1178-82). A different mutation in the same codon (c.1A>G) was reportedly identified in a Korean patient with DBA (Song MJ, Pediatr Blood Cancer 2010 Apr; 54(4):629-31). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation or N-terminal truncation, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.27
Cadd
Benign
23
Dann
Benign
0.96
DEOGEN2
Uncertain
0.74
D;D;T
Eigen
Pathogenic
0.72
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.84
D
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Uncertain
-0.15
T
MutationTaster
Benign
1.0
D;D
Vest4
0.75, 0.94
MutPred
0.94
Gain of methylation at M1 (P = 0.0013);Gain of methylation at M1 (P = 0.0013);Gain of methylation at M1 (P = 0.0013);
MVP
0.88
ClinPred
0.99
D
GERP RS
3.3
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.8
Varity_R
0.99
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0093
dbscSNV1_RF
Benign
0.088
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs116840811; hg19: chr15-83209178; API