14-49585973-C-T

Variant names:

• chr14-49585973-C-T
• rs1484307775
• NM_001032.5:c.139G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001032.5(RPS29):​c.139G>A​(p.Ala47Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A47V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RPS29 NM_001032.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.40
• Publications: 0 publications found

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]

RPS29 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 13

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS29	NM_001032.5	MANE Select	c.139G>A	p.Ala47Thr	missense	Exon 2 of 3	NP_001023.1	P62273-1
	RPS29	NM_001030001.4		c.139G>A	p.Ala47Thr	missense	Exon 2 of 3	NP_001025172.1	P62273-2
	RPS29	NM_001351375.2		c.130G>A	p.Ala44Thr	missense	Exon 2 of 3	NP_001338304.1	A0A087WTT6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS29	ENST00000245458.11	TSL:1 MANE Select	c.139G>A	p.Ala47Thr	missense	Exon 2 of 3	ENSP00000245458.7	P62273-1
	RPS29	ENST00000554075.2	TSL:1	c.139G>A	p.Ala47Thr	missense	Exon 2 of 2	ENSP00000496485.1	A0A2R8Y851
	RPS29	ENST00000396020.7	TSL:1	c.139G>A	p.Ala47Thr	missense	Exon 2 of 3	ENSP00000379339.3	P62273-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461488 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727072

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111724

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.73	T
PhyloP100		7.4
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.024	D
Polyphen		0.040	B
Vest4		0.90
MutPred		0.70		Gain of catalytic residue at Q45 (P = 0.0019)
MVP		0.30
MPC		2.4
ClinPred		1.0	D
GERP RS		5.9
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.87
gMVP		0.95
Mutation Taster		=11/89	disease causing

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: rs1484307775; hg19: chr14-50052691;