chr19-7629836-G-C

Variant names:

• chr19-7629836-G-C
• rs587777839
• NM_001171155.2:c.3G>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 18P and 1B. PVS1_Strong PS1_Moderate PS3 PP5_Very_Strong BS1_Supporting

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 (★★). ClinVar reports functional evidence for this variant: "SCV000490701: Published functional studies demonstrated the protein did not assemble into the typical complex and was not imported into the mitochondria (Lim et al., 2014)" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: PET100 NM_001171155.2 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.75
• Publications: 6 publications found

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]

STXBP2 Gene-Disease associations (from GenCC):

• familial hemophagocytic lymphohistiocytosis 5

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microvillus inclusion disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 10 codons. Genomic position: 7630573. Lost 0.126 part of the original CDS.
• PS1: Another start lost variant in NM_001171155.2 (PET100) was described as [Likely_pathogenic] in ClinVar
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000490701: Published functional studies demonstrated the protein did not assemble into the typical complex and was not imported into the mitochondria (Lim et al., 2014); SCV004297996: Experimental studies have shown that disruption of the initiator codon affects PET100 function (PMID: 24462369).
• PP5: Variant 19-7629836-G-C is Pathogenic according to our data. Variant chr19-7629836-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 125441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171155.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PET100	NM_001171155.2	MANE Select	c.3G>C	p.Met1?	start_lost	Exon 1 of 4	NP_001164626.1	P0DJ07
	STXBP2	NM_001414484.1		c.-195G>C		5_prime_UTR	Exon 1 of 21	NP_001401413.1
	PET100	NR_033242.2		n.44G>C		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PET100	ENST00000594797.6	TSL:1 MANE Select	c.3G>C	p.Met1?	start_lost	Exon 1 of 4	ENSP00000470539.1	P0DJ07
	ENSG00000268400	ENST00000698368.1		n.3G>C		non_coding_transcript_exon	Exon 1 of 20	ENSP00000513686.1	A0A8V8TM65
	PET100	ENST00000923271.1		c.3G>C	p.Met1?	start_lost	Exon 1 of 4	ENSP00000593330.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000721 AC: 1 AN: 138612 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 31556

American (AMR) AF: 0.0000282 AC: 1 AN: 35514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00 AC: 0 AN: 35728

South Asian (SAS) AF: 0.00 AC: 0 AN: 79138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35002

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5692

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078596

Other (OTH) AF: 0.0000346 AC: 2 AN: 57880

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Mitochondrial complex IV deficiency, nuclear type 12 (2)
2	-	-	not provided (2)
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)
1	-	-	PET100-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.11	T
PhyloP100		2.7
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.71
MutPred		0.67		Gain of catalytic residue at M1 (P = 0.0194)
MVP		0.099
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.90
Mutation Taster		=13/187	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777839; hg19: chr19-7694722;