rs587776629

chr17-10695739-ACT-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PM2 PP3_Moderate PP5_Very_Strong

The NM_004589.4(SCO1):c.364_364+1del variant causes a splice donor, coding sequence change. The variant allele was found at a frequency of 0.000116 in 1,600,322 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SCO1 NM_004589.4 splice_donor, coding_sequence
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.74

Genes affected

SCO1 (HGNC:10603): (synthesis of cytochrome C oxidase 1) Mammalian cytochrome c oxidase (COX) catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. In yeast, 2 related COX assembly genes, SCO1 and SCO2 (synthesis of cytochrome c oxidase), enable subunits 1 and 2 to be incorporated into the holoprotein. This gene is the human homolog to the yeast SCO1 gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.09933775 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.4, offset of 0 (no position change), new splice context is: agaGTaagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• 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 17-10695739-ACT-A is Pathogenic according to our data. Variant chr17-10695739-ACT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCO1	NM_004589.4	c.364_364+1del		splice_donor_variant, coding_sequence_variant	2/6	ENST00000255390.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCO1	ENST00000255390.10	c.364_364+1del		splice_donor_variant, coding_sequence_variant	2/6	1	NM_004589.4	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251236 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135814

Gnomad AFR exome AF: 0.0000615

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: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000113 AC: 163 AN: 1448256 Hom.: 0 AF XY: 0.000108 AC XY: 78 AN XY: 721702

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

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: 0.000142

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152066 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74278

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000121

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2022	Frameshift variant that results in protein truncation and unstable mRNA in a gene for which loss-of-function is a known mechanism of disease (PMID: 11013136); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11013136) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 28, 2022	This sequence change creates a premature translational stop signal (Splice site) in the SCO1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCO1 are known to be pathogenic (PMID: 11013136, 23878101). This variant is present in population databases (rs745552237, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with cytochrome c oxidase deficiency and/or SCO1-related conditions (PMID: 11013136). It has also been observed to segregate with disease in related individuals. This variant is also known as c.364_364+1del, △GA; nt 363–364. 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. -

Mitochondrial complex 4 deficiency, nuclear type 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 18, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2000	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 4
DS_DL_spliceai		0.98		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776629; hg19: chr17-10599056;