19-49491441-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_012423.4(RPL13A):c.419G>A(p.Arg140His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 127,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000024 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000075 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

RPL13A
NM_012423.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.63

Variant links:

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]

RPL13A links:

SNORD35A (HGNC:10162): (small nucleolar RNA, C/D box 35A) 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]

SNORD35A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a modified_residue Citrulline (size 0) in uniprot entity RL13A_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL13A	NM_012423.4 link	c.419G>A	p.Arg140His	missense_variant	Exon 7 of 8	ENST00000391857.9	NP_036555.1	P40429A0A384ME37
RPL13A	NM_001270491.2 link	c.236G>A	p.Arg79His	missense_variant	Exon 6 of 7		NP_001257420.1	P40429Q8J015
RPL13A	NR_073024.2 link	n.431G>A		non_coding_transcript_exon_variant	Exon 7 of 8
SNORD35A	NR_000018.1 link	n.*181G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL13A	ENST00000391857.9 link	c.419G>A	p.Arg140His	missense_variant	Exon 7 of 8	1	NM_012423.4	ENSP00000375730.4		P40429

Frequencies

GnomAD3 genomes

AF:

0.0000236

AC:

AN:

127250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000101

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000133

AC:

AN:

150546

AF XY:

0.0000244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000746

AC:

AN:

1072412

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

531428

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

25984

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

35092

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

21962

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

30964

Gnomad4 SAS exome

AF:

0.0000675

AC:

AN:

74090

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

31368

Gnomad4 NFE exome

AF:

0.00000373

AC:

AN:

803342

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

45784

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000236

AC:

AN:

127250

Hom.:

Cov.:

AF XY:

0.0000339

AC XY:

AN XY:

59078

show subpopulations

Gnomad4 AFR

AF:

0.0000604

AC:

0.0000604011

AN:

0.0000604011

Gnomad4 AMR

AF:

0.000101

AC:

0.000101215

AN:

0.000101215

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000892

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.419G>A (p.R140H) alteration is located in exon 7 (coding exon 7) of the RPL13A gene. This alteration results from a G to A substitution at nucleotide position 419, causing the arginine (R) at amino acid position 140 to be replaced by a histidine (H). 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

0.91

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;D

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.64

D;D

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-4.0

.;D

REVEL

Uncertain

0.48

Sift

Benign

0.066

.;T

Sift4G

Benign

0.14

T;T

Polyphen

0.032

.;B

Vest4

0.78

MutPred

0.40

.;Loss of MoRF binding (P = 0.0114);

MVP

0.79

MPC

0.59

ClinPred

0.67

GERP RS

5.7

Varity_R

0.33

gMVP

0.72

Mutation Taster

=54/46

polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over