Genetic Variant RPS26:p.Met1? (chr12-56042167-A-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001029.5(RPS26):c.1A>T(p.Met1?) variant causes a initiator codon, 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: 32)

Consequence

RPS26
NM_001029.5 initiator_codon, splice_region

Scores

Splicing: ADA: 0.8447

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.53

Publications

6 publications found

Variant links:

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]

RPS26 Gene-Disease associations (from GenCC):

Diamond-Blackfan anemia 10
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Diamond-Blackfan anemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RPS26 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-56042167-A-T is Pathogenic according to our data. Variant chr12-56042167-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS26	NM_001029.5 link	c.1A>T	p.Met1?	initiator_codon_variant, splice_region_variant	Exon 1 of 4	ENST00000646449.2	NP_001020.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RPS26	ENST00000646449.2 link	c.1A>T	p.Met1?	initiator_codon_variant, splice_region_variant	Exon 1 of 4		NM_001029.5	ENSP00000496643.1
RPS26	ENST00000356464.10 link	c.1A>T	p.Met1?	initiator_codon_variant, splice_region_variant	Exon 2 of 5	1		ENSP00000348849.5
RPS26	ENST00000552361.1 link	c.1A>T	p.Met1?	initiator_codon_variant, splice_region_variant	Exon 2 of 5	5		ENSP00000450339.1
RPS26	ENST00000548590.1 link	n.28A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Diamond-Blackfan anemia 10

Pathogenic:2

Feb 12, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, 26136524). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6123). For these reasons, this variant has been classified as Pathogenic.

not provided

Pathogenic:1

Nov 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.22

T;T;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.0

.;.;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

4.5

PROVEAN

Uncertain

-2.4

N;N;.

REVEL

Pathogenic

0.70

Sift

Uncertain

0.023

D;D;.

Sift4G

Uncertain

0.0070

D;D;.

Vest4

0.93

ClinPred

0.83

GERP RS

5.9

PromoterAI

-0.51

Under-expression

(source)

Varity_R

0.95

gMVP

0.63

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.84

dbscSNV1_RF

Benign

0.48

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over