12-56042170-G-T

Position:

• chr12-56042170-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001029.5(RPS26):​c.3+1G>T variant causes a splice donor 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS26 NM_001029.5 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.22

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 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.72126436 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.1, offset of 17, new splice context is: gtgGTgagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-56042170-G-T is Pathogenic according to our data. Variant chr12-56042170-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1798687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56042170-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS26	NM_001029.5	c.3+1G>T		splice_donor_variant		ENST00000646449.2	NP_001020.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS26	ENST00000646449.2	c.3+1G>T		splice_donor_variant			NM_001029.5	ENSP00000496643	P1
RPS26	ENST00000356464.10	c.3+1G>T		splice_donor_variant		1		ENSP00000348849	P1
RPS26	ENST00000552361.1	c.3+1G>T		splice_donor_variant		5		ENSP00000450339	P1
RPS26	ENST00000548590.1	n.30+1G>T		splice_donor_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 02, 2023

The heterozygous c.3+1G>T variant in RPS26 was identified by our study in one individual with anemia with erythroid hyperplasia, genitourinary anomalies, short stature, cleft upper lip, and cleft palate. Trio exome analysis showed this variant to be de novo. The c.3+1G>T variant in RPS26 has been previously reported in one individual with Diamond-Blackfan anemia 10 (PMID: 31401766). This variant was absent from large population studies. Two different nucleotide changes that also result in a splice donor variant at the same site, c.3+1G>A (PMID: 20116044, ClinVar Variation ID: 6126) and c.3+1G>C (PMID: 24675553), have been previously reported likely pathogenic, and the variant being assessed here, c.3+1G>T, is predicted by SpliceAI to have a similar effect on splicing. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. 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, PS1_Supporting, PS2, PS4_Supporting, PM2_Supporting (Richards 2015). -

Diamond-Blackfan anemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2018

The c.3+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 1 of the RPS26 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Two alterations at the same nucleotide position, c.3+1G>C and c.3+1G>A, have been described in unrelated probands with Diamond Blackfan anemia (DBA) (Doherty L et al. Am. J. Hum. Genet., 2010 Feb;86:222-8). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	34
DANN	Benign	0.97
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.72		Position offset: 16
DS_DL_spliceai		0.99		Position offset: -1

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: chr12-56435954; COSMIC: COSV105856382; COSMIC: COSV105856382;