12-56043440-C-T

Variant names:

• chr12-56043440-C-T
• rs148942765
• NM_001029.5:c.259C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001029.5(RPS26):​c.259C>T​(p.Arg87*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RPS26 NM_001029.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.61

Genes affected

RPS26 (HGNC:10414): (ribosomal protein S26) This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S26E family of ribosomal proteins. Mutations in this gene are found in Diamond-Blackfan anemia 10. There are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-56043440-C-T is Pathogenic according to our data. Variant chr12-56043440-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 187849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56043440-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS26	NM_001029.5	c.259C>T	p.Arg87*	stop_gained	Exon 3 of 4	ENST00000646449.2	NP_001020.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS26	ENST00000646449.2	c.259C>T	p.Arg87*	stop_gained	Exon 3 of 4		NM_001029.5	ENSP00000496643.1
RPS26	ENST00000356464.10	c.259C>T	p.Arg87*	stop_gained	Exon 4 of 5	1		ENSP00000348849.5
RPS26	ENST00000552361.1	c.259C>T	p.Arg87*	stop_gained	Exon 4 of 5	5		ENSP00000450339.1
RPS26	ENST00000548590.1	n.1046C>T		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia 10 Pathogenic:2

Jul 03, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RPS26 are known to be pathogenic (PMID: 20116044, 23718193). This variant has been observed in an individual affected with Diamond-Blackfan anaemia (PMID: 23718193). ClinVar contains an entry for this variant (Variation ID: 187849). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg87*) in the RPS26 gene. It is expected to result in an absent or disrupted protein product. -

Sep 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Diamond-Blackfan anemia 15 with mandibulofacial dysostosis Pathogenic:1

May 19, 2015

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Diamond-Blackfan anemia Pathogenic:1

Jul 07, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R87* pathogenic mutation (also known as c.259C>T), located in coding exon 3 of the RPS26 gene, results from a C to T substitution at nucleotide position 259. This changes the amino acid from an arginine to a stop codon within coding exon 3. This alteration occurs at amino acid position 87 of coding exon 3, which is the next-to-last exon of the gene, so while it is truncating, the mRNA may escape nonsense mediated decay (NMD). Premature termination codons located either in the last exon or within 50-55 nucleotides upstream of the 3'-most exon-exon junction usually fail to elicit NMD (Maquat LE. Nat. Rev. Mol. Cell Biol. 2004 Feb; 5(2):89-99). However, this mutation has been reported in multiple individuals with a clinical diagnosis of Diamond-Blackfan anemia (Gerrard G et al. Br. J. Haematol. 2013 Aug; 162(4):530-6; Chae H et al. Exp. Mol. Med. 2014 Mar; 46():e88; Gripp KW et al. Am. J. Med. Genet. A. 2014 Sep; 164A(9):2240-9). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, 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	0.58	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.92
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs148942765; hg19: chr12-56437224;