10-78033903-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_033022.4(RPS24):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. 2/3 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: RPS24 NM_033022.4 start_lost, splice_region
• Scores: Splicing: ADA: 0.8975
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.63

Genes affected

RPS24 (HGNC:10411): (ribosomal protein S24) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S24E family of ribosomal proteins. It is located in the cytoplasm. Multiple transcript variants encoding different isoforms have been found for this gene. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Mutations in this gene result in Diamond-Blackfan anemia. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-78033903-T-C is Pathogenic according to our data. Variant chr10-78033903-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1798673.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-78033903-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS24	NM_033022.4	c.2T>C	p.Met1?	start_lost, splice_region_variant	1/6	ENST00000372360.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS24	ENST00000372360.9	c.2T>C	p.Met1?	start_lost, splice_region_variant	1/6	1	NM_033022.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Feb 12, 2016

The p.M1? pathogenic mutation (also known as c.2T>C), located in coding exon 1 of the RPS24 gene, results from a T to C substitution at nucleotide position 2. This causes the loss of the initiation codon. Another alteration leading to initiation codon loss in RPS24, referred to as c.1A>G, was identified in a 26 year old female with Diamond-Blackfan anemia (DBA) who was transfusion dependent and had short stature and dysmorphic facial features. Functional studies of fibroblasts showed a reduction in protein and impaired cell growth in cells with this mutation (Badhai J et al, Biochim. Biophys. Acta 2009 Oct; 1792(10):1036-42). It was also reported in another DBA patient (Ghemlas I et al, J. Med. Genet. 2015 Sep; 52(9):575-84). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to 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	0.62	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	D;D;D;D
Polyphen		0.49, 0.78, 0.98	.;P;P;.;D;.;.;.
Vest4		0.95, 0.95, 0.94, 0.78
MutPred		0.99		Loss of stability (P = 0.0618);Loss of stability (P = 0.0618);Loss of stability (P = 0.0618);Loss of stability (P = 0.0618);Loss of stability (P = 0.0618);Loss of stability (P = 0.0618);Loss of stability (P = 0.0618);Loss of stability (P = 0.0618);
MVP		0.73
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.8
Varity_R		0.95
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Pathogenic	0.77
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: chr10-79793661;