12-56042167-A-G

Position:

• chr12-56042167-A-G

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.1A>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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS26 NM_001029.5 start_lost, splice_region
• Scores: Splicing: ADA: 0.03595
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.53

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: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-56042167-A-G is Pathogenic according to our data. Variant chr12-56042167-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 6122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56042167-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS26	NM_001029.5	c.1A>G	p.Met1?	start_lost, splice_region_variant	1/4	ENST00000646449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS26	ENST00000646449.2	c.1A>G	p.Met1?	start_lost, splice_region_variant	1/4		NM_001029.5	P1
RPS26	ENST00000356464.10	c.1A>G	p.Met1?	start_lost, splice_region_variant	2/5	1		P1
RPS26	ENST00000552361.1	c.1A>G	p.Met1?	start_lost, splice_region_variant	2/5	5		P1
RPS26	ENST00000548590.1	n.28A>G		splice_region_variant, non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia 10 Pathogenic:4

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The heterozygous p.Met1Val variant in RPS26 was identified by our study in one individual with Diamond-Blackfan anemia. The p.Met1Val variant in RPS26 has been reported in 8 unrelated individuals with Diamond-Blackfan anemia 10 (PMID: 26136524, PMID: 20116044, PMID: 24942156) and segregated with disease in 4 affected relatives from 2 families (PMID: 20116044). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 4 individuals with confirmed paternity and maternity (PMID: 24942156, PMID: 20116044). This variant has also been reported in ClinVar (Variation ID: 6122) and has been interpreted as pathogenic by OMIM, Invitae, and Ambry Genetics. Four pathogenic or likely pathogenic variants, resulting in a different amino acid change at the same position, c.1A>C (p.Met1Leu), c.1A>T (p.Met1Leu), c.2T>C (p.Met1Thr), and c.2T>G (p.Met1Arg), have been reported in ClinVar, supporting that a change at this position may not be tolerated (ClinVar Variation ID: 598993, 6123, 1798678, 933891). This variant was absent from large population studies. This variant is located in the first amino acid and obliterates the methionine initiation codon. The next in-frame methionine is at amino acid residue 115 and there are 19 reported pathogenic or likely pathogenic variants in ClinVar upstream of this downstream methionine. Heterozygous loss of function of the RPS26 gene is an established disease mechanism in Diamond-Blackfan anemia 10. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Diamond-Blackfan anemia 10. ACMG/AMP Criteria applied: PVS1_Moderate, PS2, PS4, PM2_Supporting, PP1 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 17, 2023	This sequence change affects the initiator methionine of the RPS26 mRNA. The next in-frame methionine is located at codon 115. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with Diamond-Blackfan anemia (PMID: 20116044, 24942156, 26136524). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6122). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 12, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 16, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 24, 2023

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28102861, 25525159, 28280134, 33718801, 20116044) -

Diamond-Blackfan anemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2017

The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the RPS26 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. This pathogenic mutation was first described in 4 individuals and 2 additional family members who were affected with Diamond-Blackfan anemia (Doherty L et al. Am. J. Hum. Genet., 2010 Feb;86:222-8). 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, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
DANN	Uncertain	0.97
DEOGEN2	Benign	0.35	T;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.75	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-3.0	D;D;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.026	D;D;.
Polyphen		0.26	B;B;B
Vest4		0.94
MutPred		0.67		Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);
MVP		1.0
ClinPred		0.93	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.036
dbscSNV1_RF	Benign	0.27
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.53		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs143951267; hg19: chr12-56435951; COSMIC: COSV100009401; COSMIC: COSV100009401;