NM_000977.4:c.533C>T

Variant names:

• chr16-89562939-C-T
• rs934768094
• NM_000977.4:c.533C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000977.4(RPL13):​c.533C>T​(p.Ala178Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A178D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RPL13 NM_000977.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.81
• Publications: 2 publications found

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]

RPL13 Gene-Disease associations (from GenCC):

• spondyloepimetaphyseal dysplasia, Isidor-Toutain type

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• spondyloepiphyseal dysplasia

  Inheritance: AD Classification: MODERATE Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000977.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89562939-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 813853.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.32157 (below the threshold of 3.09). Trascript score misZ: -0.64596 (below the threshold of 3.09). GenCC associations: The gene is linked to spondyloepimetaphyseal dysplasia, Isidor-Toutain type, spondyloepiphyseal dysplasia.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000977.4. 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
	RPL13	NM_000977.4	MANE Select	c.533C>T	p.Ala178Val	missense	Exon 6 of 6	NP_000968.2
	RPL13	NM_033251.2		c.533C>T	p.Ala178Val	missense	Exon 5 of 5	NP_150254.1	P26373-1
	RPL13	NM_001243131.1		c.392C>T	p.Ala131Val	missense	Exon 7 of 7	NP_001230060.1	P26373-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL13	ENST00000311528.10	TSL:1 MANE Select	c.533C>T	p.Ala178Val	missense	Exon 6 of 6	ENSP00000307889.5	P26373-1
	RPL13	ENST00000393099.4	TSL:1	c.533C>T	p.Ala178Val	missense	Exon 5 of 5	ENSP00000376811.3	P26373-1
	RPL13	ENST00000562879.5	TSL:1	n.*181C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000457174.1	H3BTH3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000423 AC: 1 AN: 236282 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000597

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: 6.92e-7 AC: 1 AN: 1445196 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718430

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32266

American (AMR) AF: 0.00 AC: 0 AN: 41294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38540

South Asian (SAS) AF: 0.00 AC: 0 AN: 83730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105366

Other (OTH) AF: 0.00 AC: 0 AN: 59578

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.026
Eigen_PC	Benign	0.063
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.26
Sift	Benign	0.15	T
Sift4G	Benign	0.19	T
Polyphen		0.064	B
Vest4		0.84
MutPred		0.72		Gain of methylation at K177 (P = 0.039)
MVP		0.71
MPC		0.26
ClinPred		0.63	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.26
gMVP		0.59

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: rs934768094; hg19: chr16-89629347;