NM_033022.4:c.46C>T

Variant names:

• chr10-78035394-C-T
• rs104894189
• NM_033022.4:c.46C>T

Variant summary

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

The NM_033022.4(RPS24):​c.46C>T​(p.Arg16*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS24 NM_033022.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.14
• Publications: 3 publications found

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]

RPS24 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Diamond-Blackfan anemia 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

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 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-78035394-C-T is Pathogenic according to our data. Variant chr10-78035394-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033022.4. 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
	RPS24	NM_033022.4	MANE Select	c.46C>T	p.Arg16*	stop_gained	Exon 2 of 6	NP_148982.1
	RPS24	NM_001142285.2		c.46C>T	p.Arg16*	stop_gained	Exon 2 of 5	NP_001135757.1
	RPS24	NM_001026.5		c.46C>T	p.Arg16*	stop_gained	Exon 2 of 5	NP_001017.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS24	ENST00000372360.9	TSL:1 MANE Select	c.46C>T	p.Arg16*	stop_gained	Exon 2 of 6	ENSP00000361435.4
	RPS24	ENST00000360830.9	TSL:1	c.46C>T	p.Arg16*	stop_gained	Exon 2 of 7	ENSP00000354074.5
	RPS24	ENST00000435275.5	TSL:2	c.46C>T	p.Arg16*	stop_gained	Exon 2 of 6	ENSP00000415549.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diamond-Blackfan anemia 3 Pathogenic:1

Dec 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Diamond-Blackfan anemia Pathogenic:1

Dec 29, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RPS24 are known to be pathogenic (PMID: 17186470, 20960466). This variant has been reported in an individual affected with Diamond-Blackfan anemia (PMID: 17186470). ClinVar contains an entry for this variant (Variation ID: 7246). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg16*) in the RPS24 gene. It is expected to result in an absent or disrupted protein product.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		3.1
Vest4		0.90
GERP RS		1.6
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs104894189; hg19: chr10-79795152;