12-56042170-G-A

Position:

• chr12-56042170-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001029.5(RPS26):​c.3+1G>A 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS26 NM_001029.5 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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 Likely_pathogenic. Variant got 7 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-A is Pathogenic according to our data. Variant chr12-56042170-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6126.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-56042170-G-A is described in Lovd as [Pathogenic]. Variant chr12-56042170-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Diamond-Blackfan anemia 10 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 12, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	34
DANN	Benign	0.97
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.78		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

LitVar

Other links and lift over

dbSNP: rs148622862; hg19: chr12-56435954;