chr19-7630584-C-A

Position:

• chr19-7630584-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001171155.2(PET100):​c.39C>A​(p.Tyr13*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PET100 NM_001171155.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.265

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]

ENSG00000268400 (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-7630584-C-A is Pathogenic according to our data. Variant chr19-7630584-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2740392.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PET100	NM_001171155.2	c.39C>A	p.Tyr13*	stop_gained	2/4	ENST00000594797.6	NP_001164626.1
STXBP2	NM_001414484.1	c.-159C>A		5_prime_UTR_variant	2/21		NP_001401413.1
PET100	NR_033242.2	n.80C>A		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PET100	ENST00000594797.6	c.39C>A	p.Tyr13*	stop_gained	2/4	1	NM_001171155.2	ENSP00000470539.1
ENSG00000268400	ENST00000698368.1	n.39C>A		non_coding_transcript_exon_variant	2/20			ENSP00000513686.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2023

This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PET100-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Tyr13*) in the PET100 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PET100 are known to be pathogenic (PMID: 24462369, 25293719, 31406627). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.57	D
Vest4		0.49
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 40
DS_AL_spliceai		0.40		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-7695470;