15-82540428-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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. 3/3 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: Splicing: ADA: 0.0004333
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.81

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]

ACMG classification

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
RPS17	NM_001021.6	c.1A>G	p.Met1?	start_lost, splice_region_variant	1/5	ENST00000647841.1
RPS17	NR_111943.2	n.30A>G		non_coding_transcript_exon_variant	1/4
RPS17	NR_111944.3	n.30A>G		splice_region_variant, non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS17	ENST00000647841.1	c.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

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 25, 2022

DNA 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 submitter

clinical testing

Ambry Genetics

Mar 25, 2015

The 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;