rs1554841994

Variant names:

• chr10-78035589-A-C
• rs1554841994
• NM_033022.4:c.148A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_033022.4(RPS24):​c.148A>C​(p.Thr50Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T50S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS24 NM_033022.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.27
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-78035589-A-C is Pathogenic according to our data. Variant chr10-78035589-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 549764.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS24	NM_033022.4	c.148A>C	p.Thr50Pro	missense_variant	Exon 3 of 6	ENST00000372360.9	NP_148982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS24	ENST00000372360.9	c.148A>C	p.Thr50Pro	missense_variant	Exon 3 of 6	1	NM_033022.4	ENSP00000361435.4
RPS24	ENST00000435275.5	c.148A>C	p.Thr50Pro	missense_variant	Exon 3 of 6	2		ENSP00000415549.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia 3 Pathogenic:1

Feb 06, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RPS24 p.T50P was confirmed de novo by sequencing both parents of an affected proband. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;.;D;.;.;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	.;D;D;.;D;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	2.9	M;.;M;.;M;.;M;M
PhyloP100		9.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.7	.;D;.;.;.;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	.;D;.;.;.;D;D;D
Sift4G	Uncertain	0.033	.;D;D;.;.;D;D;D
Polyphen		0.031, 0.10, 0.067	.;B;B;.;B;.;.;.
Vest4		0.63, 0.63, 0.63, 0.54
MutPred		0.52		Gain of methylation at K49 (P = 0.0668);Gain of methylation at K49 (P = 0.0668);Gain of methylation at K49 (P = 0.0668);Gain of methylation at K49 (P = 0.0668);Gain of methylation at K49 (P = 0.0668);Gain of methylation at K49 (P = 0.0668);Gain of methylation at K49 (P = 0.0668);Gain of methylation at K49 (P = 0.0668);
MVP		0.67
MPC		2.1
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		-0.0064	Neutral
Varity_R		0.91
gMVP		0.91
Mutation Taster		=1/99	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: rs1554841994; hg19: chr10-79795347;