12-56042168-T-C

Position:

• chr12-56042168-T-C

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>C​(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: 0.5682
• 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-C is Pathogenic according to our data. Variant chr12-56042168-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1798678.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-56042168-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS26	NM_001029.5	c.2T>C	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>C	p.Met1?	start_lost, splice_region_variant	1/4		NM_001029.5	ENSP00000496643	P1
RPS26	ENST00000356464.10	c.2T>C	p.Met1?	start_lost, splice_region_variant	2/5	1		ENSP00000348849	P1
RPS26	ENST00000552361.1	c.2T>C	p.Met1?	start_lost, splice_region_variant	2/5	5		ENSP00000450339	P1
RPS26	ENST00000548590.1	n.29T>C		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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2015

The p.M1? pathogenic mutation (also known as c.2T>C and p.M1T) is located in coding exon 1 of the RPS26 gene and results from a T to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Several disease-causing mutations have been described in the initiation codon. Since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-4.3	D;D;.
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		0.65	P;P;P
Vest4		0.95
MutPred		0.60		Gain of catalytic residue at M1 (P = 0.0082);Gain of catalytic residue at M1 (P = 0.0082);Gain of catalytic residue at M1 (P = 0.0082);
MVP		0.99
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.97
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.57
dbscSNV1_RF	Benign	0.54
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-56435952;