16-89562954-G-A

Variant names:

• chr16-89562954-G-A
• rs1597676540
• NM_000977.4:c.548G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_000977.4(RPL13):​c.548G>A​(p.Arg183His) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RPL13 NM_000977.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 9.88

Genes affected

RPL13 (HGNC:10303): (ribosomal protein L13) 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 60S subunit. The protein belongs to the L13E family of ribosomal proteins. It is located in the cytoplasm. This gene is expressed at significantly higher levels in benign breast lesions than in breast carcinomas. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89562954-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 16-89562954-G-A is Pathogenic according to our data. Variant chr16-89562954-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1030926.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL13	NM_000977.4	c.548G>A	p.Arg183His	missense_variant	Exon 6 of 6	ENST00000311528.10	NP_000968.2
RPL13	NM_033251.2	c.548G>A	p.Arg183His	missense_variant	Exon 5 of 5		NP_150254.1
RPL13	NM_001243131.1	c.407G>A	p.Arg136His	missense_variant	Exon 7 of 7		NP_001230060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL13	ENST00000311528.10	c.548G>A	p.Arg183His	missense_variant	Exon 6 of 6	1	NM_000977.4	ENSP00000307889.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000138 AC: 2 AN: 1447598 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719432

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spondyloepimetaphyseal dysplasia, Isidor-Toutain type Pathogenic:2 Uncertain:2

Mar 22, 2022

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000689803,VCV000804147, PMID:31630789). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Sep 11, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

May 16, 2021

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A novel missense variant, c.548G>A in exon 6 of RPL13, was observed in heterozygous state in proband and in other affected family members. The variant is absent in gnomAD population database and in our in-house database of 1144 exomes. In-silico analysis tools (Mutation Taster, SIFT and REVEL) are consistent in predicting that the variant is damaging to RPL13 protein function. Clinical findings are in concordance with Spondyloepimetaphyseal dsyplasia, Isidor-Toutain type, thus the variant is interpreted to be likely pathogenic for the affected individuals. -

Jul 25, 2022

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg183His variant in RPL13 was absent from large population studies (gnomAD). Another variant affecting the same amino acid residue (p.Arg183Pro) has previously been reported in one individual with SEMDIST (OMIM #618728, Le Caignec et al. 2015). The variant has a accession number in ClinVar (SCV001984874) and classified as likely pathogenic. This variant was seen in an affected individual and her affected mother. In summary, the Arg183His meets our criterua to be classified as likely pathogenic. -

not provided Pathogenic:1 Uncertain:1

Jan 25, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37121912, 37993442) -

Jul 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg183 amino acid residue in RPL13. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31630789). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). ClinVar contains an entry for this variant (Variation ID: 1030926). This variant has not been reported in the literature in individuals affected with RPL13-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 183 of the RPL13 protein (p.Arg183His). -

RPL13-related disorder Pathogenic:1

May 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RPL13 c.548G>A variant is predicted to result in the amino acid substitution p.Arg183His. This variant has been reported in a mother and child with spondyloepimetaphyseal dysplasia and was reported to be de novo in the mother (Díaz-González et al. 2023. PubMed ID: 37121912). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has conflicting interpretations in ClinVar of uncertain and likely pathogenic (https://ncbi.nlm.nih.gov/clinvar/variation/1030926/). Of note, a different missense variant affecting this amino acid (p.Arg183Pro) has been reported in an individual with spondyloepimetaphyseal dysplasia (Le Caignec et al. 2019. PubMed ID: 31630789). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;T;.;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;.;D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.7	M;.;M;.;M
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Benign	0.039	D;T;D;D;D
Sift4G	Uncertain	0.038	D;T;D;T;D
Polyphen		0.13	B;.;B;.;B
Vest4		0.80
MutPred		0.75		Loss of methylation at R183 (P = 0.0203);.;Loss of methylation at R183 (P = 0.0203);.;Loss of methylation at R183 (P = 0.0203);
MVP		0.90
MPC		0.30
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.34
gMVP		0.69

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: rs1597676540; hg19: chr16-89629362;