rs116840811

Variant names:

• chr15-82540427-A-C
• rs116840811
• NM_001021.6:c.2T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_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. 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: 0.009343
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.19

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]

ENSG00000260836 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• 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 rank	MANE	Protein	UniProt
RPS17	NM_001021.6	c.2T>G	p.Met1?	start_lost, splice_region_variant	Exon 1 of 5	ENST00000647841.1	NP_001012.1
RPS17	NR_111943.2	n.31T>G		non_coding_transcript_exon_variant	Exon 1 of 4
RPS17	NR_111944.3	n.31T>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS17	ENST00000647841.1	c.2T>G	p.Met1?	start_lost, splice_region_variant	Exon 1 of 5		NM_001021.6	ENSP00000498019.1
ENSG00000260836	ENST00000562833.2	c.1351-295T>G		intron_variant	Intron 9 of 12	3		ENSP00000454786.2

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

Diamond-Blackfan anemia 4 Pathogenic:1

Dec 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Diamond-Blackfan anemia Pathogenic:1

Oct 14, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	-0.15	T
PROVEAN	Uncertain	-4.2	.;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;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

Other links and lift over

dbSNP: rs116840811; hg19: chr15-83209178;