NM_001029.5:c.55C>T

Variant names:

• chr12-56042476-C-T
• rs797045919
• NM_001029.5:c.55C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001029.5(RPS26):​c.55C>T​(p.Gln19*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS26 NM_001029.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.46
• Publications: 3 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-56042476-C-T is Pathogenic according to our data. Variant chr12-56042476-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 212066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS26	NM_001029.5	MANE Select	c.55C>T	p.Gln19*	stop_gained	Exon 2 of 4	NP_001020.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS26	ENST00000646449.2	MANE Select	c.55C>T	p.Gln19*	stop_gained	Exon 2 of 4	ENSP00000496643.1
	RPS26	ENST00000356464.10	TSL:1	c.55C>T	p.Gln19*	stop_gained	Exon 3 of 5	ENSP00000348849.5
	RPS26	ENST00000552361.1	TSL:5	c.55C>T	p.Gln19*	stop_gained	Exon 3 of 5	ENSP00000450339.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Diamond-Blackfan anemia 10 (2)
1	-	-	Diamond-Blackfan anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		7.5
Vest4		0.78
GERP RS		4.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs797045919; hg19: chr12-56436260;