19-5678647-GC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_StrongPM2PP3_ModeratePP5

The NM_205767.3(MICOS13):c.260del(p.Gly87AlafsTer3) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.00000458 in 1,529,544 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

MICOS13
NM_205767.3 frameshift, splice_region

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 4.63

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.272 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 19-5678647-GC-G is Pathogenic according to our data. Variant chr19-5678647-GC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1007450.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MICOS13	NM_205767.3 linkuse as main transcript	c.260del	p.Gly87AlafsTer3	frameshift_variant, splice_region_variant	4/4	ENST00000309324.9
MICOS13	NM_001308240.2 linkuse as main transcript	c.326del	p.Gly109AlafsTer3	frameshift_variant, splice_region_variant	5/5
MICOS13	NM_001365761.2 linkuse as main transcript	c.326del	p.Gly109AlafsTer3	frameshift_variant, splice_region_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MICOS13	ENST00000309324.9 linkuse as main transcript	c.260del	p.Gly87AlafsTer3	frameshift_variant, splice_region_variant	4/4	1	NM_205767.3	P1
MICOS13	ENST00000587950.5 linkuse as main transcript	c.326del	p.Gly109AlafsTer3	frameshift_variant, splice_region_variant	4/4	2
RPL36	ENST00000579649.5 linkuse as main transcript	c.-60+3677del		intron_variant		5		P1
MICOS13	ENST00000585605.1 linkuse as main transcript	n.359del		splice_region_variant, non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD3 exomes

AF:

0.0000307

AC:

AN:

130318

Hom.:

AF XY:

0.0000291

AC XY:

AN XY:

68810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000140

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000210

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000363

AC:

AN:

1377456

Hom.:

Cov.:

AF XY:

0.00000295

AC XY:

AN XY:

678712

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000914

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:

9.36e-7

Gnomad4 OTH exome

AF:

0.0000175

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000480

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2018	This sequence change¬†results in a premature translational stop signal in the C19orf70 gene¬†(p.Gly87Alafs3).¬†While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acids of the C19orf70 protein.¬†The C19orf70 gene has multiple transcripts. The c.260delG (p.Gly87Alafs3) variant occurs in alternate transcript¬†NM_205767.2, which corresponds to¬†c.326delG (p.Gly109Alafs*3) in NM_001308240.1, the primary transcript listed in the Methods. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with C19orf70-related disease. 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. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2023	Frameshift variant predicted to result in protein truncation, as the last 32 amino acids are replaced with 2 different amino acids, and another loss-of-function variant affecting the last exon has been reported in the published literature (Godiker et al., 2018); This variant is associated with the following publications: (PMID: 30912852) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: 0

DS_AL_spliceai

1.0

Position offset: 1

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