rs587777839

Positions:

chr19-7629836-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001171155.2(PET100):c.3G>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000795 in 1,384,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

PET100
NM_001171155.2 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.75

Variant links:

Genes affected

PET100 (HGNC:40038): (PET100 cytochrome c oxidase chaperone) Mitochondrial complex IV, or cytochrome c oxidase, is a large transmembrane protein complex that is part of the respiratory electron transport chain of mitochondria. The small protein encoded by this gene plays a role in the biogenesis of mitochondrial complex IV. This protein localizes to the inner mitochondrial membrane and is exposed to the intermembrane space. Mutations in this gene are associated with mitochondrial complex IV deficiency. This gene has a pseudogene on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

PET100 links:

STXBP2 (HGNC:):

STXBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-7629836-G-C is Pathogenic according to our data. Variant chr19-7629836-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 125441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7629836-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PET100	NM_001171155.2 linkuse as main transcript	c.3G>C	p.Met1?	start_lost	1/4	ENST00000594797.6	NP_001164626.1
STXBP2	NM_001414484.1 linkuse as main transcript	c.-195G>C		5_prime_UTR_variant	1/21		NP_001401413.1
PET100	NR_033242.2 linkuse as main transcript	n.44G>C		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PET100	ENST00000594797.6 linkuse as main transcript	c.3G>C	p.Met1?	start_lost	1/4	1	NM_001171155.2	ENSP00000470539	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000721

AC:

AN:

138612

Hom.:

AF XY:

0.00

AC XY:

AN XY:

74336

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000795

AC:

AN:

1384244

Hom.:

Cov.:

AF XY:

0.00000439

AC XY:

AN XY:

683058

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000282

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:

0.00000185

Gnomad4 OTH exome

AF:

0.0000346

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	Founder variant in Lebanese individuals with Leigh syndrome (Lim et al., 2014); Published functional studies demonstrated the protein did not assemble into the typical complex and was not imported into the mitochondria (Lim et al., 2014); This variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1? using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26506407, 24462369, 31406627, 32313153) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 05, 2023	Experimental studies have shown that disruption of the initiator codon affects PET100 function (PMID: 24462369). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 125441). Disruption of the initiator codon has been observed in individuals with PET100-related conditions (PMID: 24462369, 32313153). It is commonly reported in individuals of Lebanese ancestry (PMID: 24462369, 31406627). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change affects the initiator methionine of the PET100 mRNA. The next in-frame methionine is located at codon 10. -

Mitochondrial complex 4 deficiency, nuclear type 12

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 26, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 06, 2014	- -

Mitochondrial complex IV deficiency, nuclear type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Kids Research, The Children's Hospital at Westmead

- -

PET100-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2024

The PET100 c.3G>C variant is predicted to disrupt the translation initiation site (Start Loss). This variant was reported as a Lebanese founder variant in individuals with Leigh syndrome (see, for example, Lim et al. 2014. PubMed ID: 24462369; Riley et al. 2020. PubMed ID: 32313153). This variant is reported in 0.0040% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/). Taken together, we classify this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.081

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Uncertain

-0.11

MutationTaster

Benign

0.99

PROVEAN

Uncertain

-3.0

.;D;.

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.91

P;.;.

Vest4

0.71

MutPred

0.67

Gain of catalytic residue at M1 (P = 0.0194);Gain of catalytic residue at M1 (P = 0.0194);Gain of catalytic residue at M1 (P = 0.0194);

MVP

0.099

ClinPred

0.99

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.90

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