19-49490790-C-T

Variant names:

• chr19-49490790-C-T
• NM_012423.4:c.268C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012423.4(RPL13A):​c.268C>T​(p.His90Tyr) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPL13A NM_012423.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

Genes affected

RPL13A (HGNC:10304): (ribosomal protein L13a) 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 member of the L13P family of ribosomal proteins that is a component of the 60S subunit. The encoded protein also plays a role in the repression of inflammatory genes as a component of the IFN-gamma-activated inhibitor of translation (GAIT) complex. This gene is co-transcribed with the small nucleolar RNA genes U32, U33, U34, and U35, which are located in the second, fourth, fifth, and sixth introns, respectively. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed throughout the genome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

SNORD34 (HGNC:10161): (small nucleolar RNA, C/D box 34) Predicted to act upstream of or within glucose metabolic process; insulin secretion; and reactive oxygen species metabolic process. [provided by Alliance of Genome Resources, Apr 2022]

SNORD33 (HGNC:10160): (small nucleolar RNA, C/D box 33) Predicted to act upstream of or within glucose metabolic process; insulin secretion; and reactive oxygen species metabolic process. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL13A	NM_012423.4	c.268C>T	p.His90Tyr	missense_variant	Exon 5 of 8	ENST00000391857.9	NP_036555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL13A	ENST00000391857.9	c.268C>T	p.His90Tyr	missense_variant	Exon 5 of 8	1	NM_012423.4	ENSP00000375730.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.268C>T (p.H90Y) alteration is located in exon 5 (coding exon 5) of the RPL13A gene. This alteration results from a C to T substitution at nucleotide position 268, causing the histidine (H) at amino acid position 90 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.9	.;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.6	.;D
REVEL	Benign	0.28
Sift	Uncertain	0.015	.;D
Sift4G	Benign	0.16	T;T
Polyphen		0.99	.;D
Vest4		0.82
MutPred		0.60		.;Loss of methylation at K91 (P = 0.0587);
MVP		0.57
MPC		1.4
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49994047;