14-49586039-A-G

Variant names:

• chr14-49586039-A-G
• rs1064795244
• NM_001032.5:c.73T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001032.5(RPS29):​c.73T>C​(p.Ser25Pro) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS29 NM_001032.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-49586039-A-G is Pathogenic according to our data. Variant chr14-49586039-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421606.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS29	NM_001032.5	c.73T>C	p.Ser25Pro	missense_variant	Exon 2 of 3	ENST00000245458.11	NP_001023.1
RPS29	NM_001030001.4	c.73T>C	p.Ser25Pro	missense_variant	Exon 2 of 3		NP_001025172.1
RPS29	NM_001351375.2	c.64T>C	p.Ser22Pro	missense_variant	Exon 2 of 3		NP_001338304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS29	ENST00000245458.11	c.73T>C	p.Ser25Pro	missense_variant	Exon 2 of 3	1	NM_001032.5	ENSP00000245458.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 30, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The S25P variant in the RPS29 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S25P variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S25P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret S25P as a likely pathogenic variant -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D;D;T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.87	D;.;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.1	D;D;.;.;.;.
REVEL	Benign	0.29
Sift	Uncertain	0.021	D;D;.;.;.;.
Sift4G	Uncertain	0.045	D;D;.;T;.;.
Polyphen		0.45	.;B;B;.;.;.
Vest4		0.90
MutPred		0.53		Gain of catalytic residue at L30 (P = 0);Gain of catalytic residue at L30 (P = 0);Gain of catalytic residue at L30 (P = 0);.;Gain of catalytic residue at L30 (P = 0);.;
MVP		0.21
MPC		2.5
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.95

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: rs1064795244; hg19: chr14-50052757;