rs587777569

chr14-49585963-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_001032.5(RPS29):c.149T>C(p.Ile50Thr) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS29 NM_001032.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.75

Genes affected

RPS29 (HGNC:10419): (ribosomal protein S29) 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 and a member of the S14P family of ribosomal proteins. The protein, which contains a C2-C2 zinc finger-like domain that can bind to zinc, can enhance the tumor suppressor activity of Ras-related protein 1A (KREV1). It is located in the cytoplasm. Variable expression of this gene in colorectal cancers compared to adjacent normal tissues has been observed, although no correlation between the level of expression and the severity of the disease has been found. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain 40S ribosomal protein S29 (size 54) in uniprot entity RS29_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001032.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811
• PP5: Variant 14-49585963-A-G is Pathogenic according to our data. Variant chr14-49585963-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140739.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS29	NM_001032.5	c.149T>C	p.Ile50Thr	missense_variant	2/3	ENST00000245458.11
RPS29	NM_001030001.4	c.149T>C	p.Ile50Thr	missense_variant	2/3
RPS29	NM_001351375.2	c.140T>C	p.Ile47Thr	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS29	ENST00000245458.11	c.149T>C	p.Ile50Thr	missense_variant	2/3	1	NM_001032.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia 13 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jun 26, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 03, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	26
Dann	Uncertain	0.98
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D;.;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.8	D;D;.;.;.;.
REVEL	Pathogenic	0.70
Sift	Benign	0.045	D;T;.;.;.;.
Sift4G	Benign	0.061	T;T;.;T;.;.
Polyphen		0.0060	.;B;B;.;.;.
Vest4		0.95
MutPred		0.66		Gain of catalytic residue at Q45 (P = 0.0013);Gain of catalytic residue at Q45 (P = 0.0013);Gain of catalytic residue at Q45 (P = 0.0013);.;Gain of catalytic residue at Q45 (P = 0.0013);.;
MVP		0.50
MPC		2.6
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.70
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777569; hg19: chr14-50052681;