rs267607023

Variant names:

• chr12-56042518-G-A
• rs267607023
• NM_001029.5:c.97G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001029.5(RPS26):​c.97G>A​(p.Asp33Asn) variant causes a missense 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D33V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS26 NM_001029.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.50
• Publications: 5 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.932 (below the threshold of 3.09). Trascript score misZ: 2.7361 (below the threshold of 3.09). GenCC associations: The gene is linked to Diamond-Blackfan anemia 10, Diamond-Blackfan anemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 12-56042518-G-A is Pathogenic according to our data. Variant chr12-56042518-G-A is described in CliVar as Pathogenic. Clinvar id is 6124.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-56042518-G-A is described in CliVar as Pathogenic. Clinvar id is 6124.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-56042518-G-A is described in CliVar as Pathogenic. Clinvar id is 6124.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-56042518-G-A is described in CliVar as Pathogenic. Clinvar id is 6124.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-56042518-G-A is described in CliVar as Pathogenic. Clinvar id is 6124.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS26	NM_001029.5	c.97G>A	p.Asp33Asn	missense_variant	Exon 2 of 4	ENST00000646449.2	NP_001020.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS26	ENST00000646449.2	c.97G>A	p.Asp33Asn	missense_variant	Exon 2 of 4		NM_001029.5	ENSP00000496643.1
RPS26	ENST00000356464.10	c.97G>A	p.Asp33Asn	missense_variant	Exon 3 of 5	1		ENSP00000348849.5
RPS26	ENST00000552361.1	c.97G>A	p.Asp33Asn	missense_variant	Exon 3 of 5	5		ENSP00000450339.1
RPS26	ENST00000548590.1	n.124G>A		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Feb 12, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	.;.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.78	D
PhyloP100		9.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.9	D;D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.024	D;D;.
Sift4G	Uncertain	0.025	D;D;.
Polyphen		0.88	P;P;P
Vest4		0.95
MutPred		0.85		Gain of catalytic residue at R28 (P = 0.0279);Gain of catalytic residue at R28 (P = 0.0279);Gain of catalytic residue at R28 (P = 0.0279);
MVP		0.96
MPC		2.4
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.80
gMVP		0.89
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs267607023; hg19: chr12-56436302;