19-7629836-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PVS1_ModeratePM2PP5_Very_StrongBS1_Supporting

The NM_001171155.2(PET100):ā€‹c.3G>Cā€‹(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 (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000079 ( 0 hom. )

Consequence

PET100
NM_001171155.2 start_lost

Scores

5
8
3

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]
STXBP2 (HGNC:11445): (syntaxin binding protein 2) This gene encodes a member of the STXBP/unc-18/SEC1 family. The encoded protein is involved in intracellular trafficking, control of SNARE (soluble NSF attachment protein receptor) complex assembly, and the release of cytotoxic granules by natural killer cells. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 27 CDS bases. Genomic position: 7629860. Lost 0.122 part of the original CDS.
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].
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000795 (11/1384244) while in subpopulation MID AF= 0.00105 (6/5692). AF 95% confidence interval is 0.000459. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PET100NM_001171155.2 linkc.3G>C p.Met1? start_lost Exon 1 of 4 ENST00000594797.6 NP_001164626.1 P0DJ07
STXBP2NM_001414484.1 linkc.-195G>C 5_prime_UTR_variant Exon 1 of 21 NP_001401413.1
PET100NR_033242.2 linkn.44G>C non_coding_transcript_exon_variant Exon 1 of 5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PET100ENST00000594797.6 linkc.3G>C p.Met1? start_lost Exon 1 of 4 1 NM_001171155.2 ENSP00000470539.1 P0DJ07
ENSG00000268400ENST00000698368.1 linkn.3G>C non_coding_transcript_exon_variant Exon 1 of 20 ENSP00000513686.1 A0A8V8TM65

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000721
AC:
1
AN:
138612
Hom.:
0
AF XY:
0.00
AC XY:
0
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:
11
AN:
1384244
Hom.:
0
Cov.:
31
AF XY:
0.00000439
AC XY:
3
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.:
31
Alfa
AF:
0.0000936
Hom.:
0
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
Aug 05, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects the initiator methionine of the PET100 mRNA. The next in-frame methionine is located at codon 10. This variant is present in population databases (no rsID available, gnomAD 0.004%). 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). ClinVar contains an entry for this variant (Variation ID: 125441). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. 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. -

Nov 03, 2020
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Mitochondrial complex 4 deficiency, nuclear type 12 Pathogenic:2
Feb 06, 2014
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

May 26, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
-
Kids Research, The Children's Hospital at Westmead
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

PET100-related disorder Pathogenic:1
Mar 07, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
D
BayesDel_noAF
Uncertain
0.12
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;.;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Benign
0.081
D
MetaRNN
Pathogenic
0.75
D;D;D
MetaSVM
Uncertain
-0.11
T
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
D
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.

Other links and lift over

dbSNP: rs587777839; hg19: chr19-7694722; API