12-56042168-T-G

Position:

• chr12-56042168-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_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
• Scores: Splicing: ADA: 0.8103
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• 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	Protein	UniProt
RPS26	NM_001029.5	c.2T>G	p.Met1?	start_lost, splice_region_variant	1/4	ENST00000646449.2	NP_001020.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS26	ENST00000646449.2	c.2T>G	p.Met1?	start_lost, splice_region_variant	1/4		NM_001029.5	ENSP00000496643.1
RPS26	ENST00000356464.10	c.2T>G	p.Met1?	start_lost, splice_region_variant	2/5	1		ENSP00000348849.5
RPS26	ENST00000552361.1	c.2T>G	p.Met1?	start_lost, splice_region_variant	2/5	5		ENSP00000450339.1
RPS26	ENST00000548590.1	n.29T>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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.41	T;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.3	D;D;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		0.82	P;P;P
Vest4		0.95
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		0.98
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.81
dbscSNV1_RF	Benign	0.52
SpliceAI score (max)		0.020		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: rs1895894261; hg19: chr12-56435952;