12-56042168-T-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001029.5(RPS26):c.2T>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: 32)
Consequence
RPS26
NM_001029.5 start_lost, splice_region
NM_001029.5 start_lost, splice_region
Scores
9
2
4
Splicing: ADA: 0.8103
2
Clinical Significance
Conservation
PhyloP100: 2.62
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]
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ACMG classification
Classification made for transcript
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 12-56042168-T-G is Pathogenic according to our data. Variant chr12-56042168-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 933891.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-56042168-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPS26 | NM_001029.5 | c.2T>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.2T>G | p.Met1? | start_lost, splice_region_variant | 1/4 | NM_001029.5 | P1 | ||
RPS26 | ENST00000356464.10 | c.2T>G | p.Met1? | start_lost, splice_region_variant | 2/5 | 1 | P1 | ||
RPS26 | ENST00000552361.1 | c.2T>G | p.Met1? | start_lost, splice_region_variant | 2/5 | 5 | P1 | ||
RPS26 | ENST00000548590.1 | n.29T>G | splice_region_variant, non_coding_transcript_exon_variant | 1/3 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Diamond-Blackfan anemia 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2019 | This sequence change affects the initiator methionine of the RPS26 mRNA. The next in-frame methionine is located at the penultimate codon of the RPS26 gene. This variant is not present in population databases (ExAC no frequency). Disruption of the initiator codon has been observed in individuals with clinical features of Diamond-Blackfan anemia (PMID: 20116044, 21414820, 26136524, 28102861, 29114930). In at least one individual the variant was observed to be de novo. Loss-of-function variants in RPS26 are known to be pathogenic (PMID: 20116044, 23718193). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Benign
DEOGEN2
Benign
T;T;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
PROVEAN
Uncertain
D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;.
Polyphen
P;P;P
Vest4
MutPred
Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at