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GeneBe

15-82540428-T-C

Variant summary

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

The NM_001021.6(RPS17):c.1A>G(p.Met1?) variant causes a start lost, splice region change involving the alteration of a non-conserved nucleotide. 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: 0.0004333
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.81
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 15-82540428-T-C is Pathogenic according to our data. Variant chr15-82540428-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1784170.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.1A>G p.Met1? start_lost, splice_region_variant 1/5 ENST00000647841.1
RPS17NR_111943.2 linkuse as main transcriptn.30A>G non_coding_transcript_exon_variant 1/4
RPS17NR_111944.3 linkuse as main transcriptn.30A>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.1A>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

not provided Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoFeb 25, 2022DNA sequence analysis of the RPS17 gene demonstrated a sequence change, c.1A>G, in exon 1 that impacts the initiator methionine of the RPS17 mRNA. This sequence change may result in an absent or abnormal transcript. This sequence change has been reported in an individual with a diagnosis of Diamond-Blackfan anemia and it was confirmed to be de novo (PMID: 19953637). Additionally, a different sequence change also impacting the initiation codon, c.2T>G, was identified as a de novo variant in a patient with Diamond-Blackfan anemia presenting as macrocytic anemia with increased activity of erythrocyte adenosine deaminase, short stature, facial dysmorphism, and a flat thenar eminence (PMID: 17647292). This sequence change has not been described in population databases such as ExAC and gnomAD. Based on these evidences, this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively. -
Diamond-Blackfan anemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 25, 2015The p.M1? pathogenic mutation (also known as c.1A>G), located in coding exon 1 of the RPS17 gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. This mutation has been described to occur de novo in an infant with a clinical diagnosis of Diamond Blackfan Anemia (Song MJ, Pediatr Blood Cancer 2010 Apr; 54(4):629-31). In addition to the clinical data presented in the literature, 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
0.31
D
BayesDel_noAF
Pathogenic
0.21
Cadd
Benign
21
Dann
Benign
0.95
DEOGEN2
Uncertain
0.62
D;D;T
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.85
D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Uncertain
-0.045
T
MutationTaster
Benign
1.0
D;D
Vest4
0.57, 0.58
MutPred
0.94
Loss of methylation at R3 (P = 0.1525);Loss of methylation at R3 (P = 0.1525);Loss of methylation at R3 (P = 0.1525);
MVP
0.78
ClinPred
0.77
D
GERP RS
3.3
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.2
Varity_R
0.96
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00043
dbscSNV1_RF
Benign
0.020
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-83209179; API