Variant 19-5679642-CG-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_205767.3(MICOS13):c.150del(p.Ala51ProfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MICOS13
NM_205767.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: -6.75

Variant links:

Genes affected

MICOS13 (HGNC:33702): (mitochondrial contact site and cristae organizing system subunit 13) Involved in cristae formation. Located in mitochondrial crista junction and nucleoplasm. Part of MICOS complex. Implicated in combined oxidative phosphorylation deficiency 37. [provided by Alliance of Genome Resources, Apr 2022]

MICOS13 links:

RPL36 (HGNC:13631): (ribosomal protein L36) 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 L36E family of ribosomal proteins. It is located in the cytoplasm. Transcript variants derived from alternative splicing exist; they encode the same protein. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

RPL36 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-5679642-CG-C is Pathogenic according to our data. Variant chr19-5679642-CG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1526386.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MICOS13	NM_205767.3 linkuse as main transcript	c.150del	p.Ala51ProfsTer39	frameshift_variant	2/4	ENST00000309324.9
MICOS13	NM_001308240.2 linkuse as main transcript	c.216del	p.Ala73ProfsTer39	frameshift_variant	3/5
MICOS13	NM_001365761.2 linkuse as main transcript	c.216del	p.Ala73ProfsTer39	frameshift_variant	2/4
MICOS13	XM_011527675.3 linkuse as main transcript	c.216del	p.Ala73ProfsTer59	frameshift_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MICOS13	ENST00000309324.9 linkuse as main transcript	c.150del	p.Ala51ProfsTer39	frameshift_variant	2/4	1	NM_205767.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1458530

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725620

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2024

Frameshift variant predicted to result in abnormal protein length as the last 68 amino acids are replaced with 38 different amino acids, and other similar variants have been reported in HGMD; Has not been previously published as pathogenic or benign to our knowledge -

Combined oxidative phosphorylation deficiency 37

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Royal Medical Services, Bahrain Defence Force Hospital

The MICOS13 variant c.150del p.(Ala51Profs*39) creates a shift in the reading frame starting at codon 51 in exon(s) no. 2 (of 4). To the best of our knowledge this is a novel variant not previously reported in the literature. ClinVar lists this variant (Interpretation: Likely pathogenic; Variation ID: 1526386). It is classified as variant of uncertain significance based on the ACMG/AMP/ClinGen SVI guidelines. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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