9-133352138-GCTCT-GCT
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_003172.4(SURF1):c.754_755del(p.Ser252HisfsTer39) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000438 in 1,597,582 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000042 ( 0 hom. )
Consequence
SURF1
NM_003172.4 frameshift, splice_region
NM_003172.4 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.43
Genes affected
SURF1 (HGNC:11474): (SURF1 cytochrome c oxidase assembly factor) This gene encodes a protein localized to the inner mitochondrial membrane and thought to be involved in the biogenesis of the cytochrome c oxidase complex. The protein is a member of the SURF1 family, which includes the related yeast protein SHY1 and rickettsial protein RP733. The gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity, where it shares a bidirectional promoter with SURF2 on the opposite strand. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-133352138-GCT-G is Pathogenic according to our data. Variant chr9-133352138-GCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 365526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SURF1 | NM_003172.4 | c.754_755del | p.Ser252HisfsTer39 | frameshift_variant, splice_region_variant | 8/9 | ENST00000371974.8 | NP_003163.1 | |
| SURF1 | NM_001280787.1 | c.427_428del | p.Ser143HisfsTer39 | frameshift_variant, splice_region_variant | 7/8 | NP_001267716.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SURF1 | ENST00000371974.8 | c.754_755del | p.Ser252HisfsTer39 | frameshift_variant, splice_region_variant | 8/9 | 1 | NM_003172.4 | ENSP00000361042 | P1 | |
| SURF1 | ENST00000615505.4 | c.427_428del | p.Ser143HisfsTer39 | frameshift_variant, splice_region_variant | 7/8 | 1 | ENSP00000482067 | |||
| SURF1 | ENST00000437995.1 | n.664_665del | splice_region_variant, non_coding_transcript_exon_variant | 7/8 | 5 | |||||
| SURF1 | ENST00000495952.5 | n.744_745del | splice_region_variant, non_coding_transcript_exon_variant | 4/5 | 2 |
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GnomAD3 genomes 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000454 AC: 1AN: 220304Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 118762
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GnomAD4 exome AF: 0.00000415 AC: 6AN: 1445378Hom.: 0 AF XY: 0.00000418 AC XY: 3AN XY: 717380
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GnomAD4 genome 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74338
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Leigh syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 06, 2021 | Variant summary: SURF1 c.754_755delAG (p.Ser252HisfsX39) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.5e-06 in 220304 control chromosomes. c.754_755delAG has been reported in the literature in multiple compound heterozygous and a homozygous individual affected with Leigh Syndrome (Tanigawa 2012, Wedatilake 2013, Rodinova 2014, Li 2018). These data indicate that the variant is likely to be associated with disease. Publications also reported that the variant results in low muscle cytochrome c oxidase (COX) activity in patients (Wedatilake 2013, Rodinova 2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | This sequence change creates a premature translational stop signal (p.Ser252Hisfs*39) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the SURF1 protein. This variant is present in population databases (rs782007828, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex IV deficiency (PMID: 22410471, 30872186). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.752_753del. ClinVar contains an entry for this variant (Variation ID: 365526). This variant disrupts a region of the SURF1 protein in which other variant(s) (p.Ser282Cysfs*9) have been determined to be pathogenic (PMID: 9837813, 16326995, 18583168, 22488715, 23829769). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The SURF1 c.754_755delAG (p.Ser252HisfsTer39) variant, also known as c.752_753delAG, is a frameshift variant predicted to result in premature termination of the protein. The variant was first reported by Tanigawa et al. (2012) in a compound heterozygous state with a splice site variant in an individual with Leigh syndrome. Wedatilake et al. (2013) identified the c.754_755delAG variant in a homozygous state in one individual who had low muscle cytochrome c oxidase (COX) activity. Rodinová et al. (2014) described a third affected individual who was a compound heterozygote for the c.754_755delAG variant and another frameshift variant. The authors demonstrated that the amount and activity of complex IV (COX) in the fibroblasts of this patient was greatly reduced compared to that of healthy controls. Control data are unavailable for this variant, which is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is from one allele in a region of low coverage. Based on the evidence from the literature and the potential impact of frameshift variants, the p.Ser252HisfsTer39 variant is interpreted as likely pathogenic for Leigh syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift c.754_755del (p.Ser252HisfsTer39) variant has been reported in the literature in multiple compound heterozygous and a homozygous individual affected with Leigh Syndrome (Tanigawa J et al). This p.Ser252HisfsTer39 variant has allele frequency of 0.00045% in the gnomAD and novel (not in any individuals) in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Serine 252, changes this amino acid to Histidine residue, and creates a premature Stop codon at position 39 of the new reading frame, denoted p.Ser252HisfsTer39. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at