rs864309500
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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.799_800delCT(p.Leu267fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,458,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
SURF1
NM_003172.4 frameshift
NM_003172.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.84
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. Fraction of 0.115 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-133352093-CAG-C is Pathogenic according to our data. Variant chr9-133352093-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133352093-CAG-C is described in Lovd as [Pathogenic]. Variant chr9-133352093-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SURF1 | NM_003172.4 | c.799_800delCT | p.Leu267fs | frameshift_variant | 8/9 | ENST00000371974.8 | NP_003163.1 | |
SURF1 | NM_001280787.1 | c.472_473delCT | p.Leu158fs | frameshift_variant | 7/8 | NP_001267716.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SURF1 | ENST00000371974.8 | c.799_800delCT | p.Leu267fs | frameshift_variant | 8/9 | 1 | NM_003172.4 | ENSP00000361042.3 | ||
SURF1 | ENST00000615505.4 | c.472_473delCT | p.Leu158fs | frameshift_variant | 7/8 | 1 | ENSP00000482067.1 | |||
SURF1 | ENST00000437995.1 | n.709_710delCT | non_coding_transcript_exon_variant | 7/8 | 5 | |||||
SURF1 | ENST00000495952.5 | n.789_790delCT | non_coding_transcript_exon_variant | 4/5 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000411 AC: 1AN: 243518Hom.: 0 AF XY: 0.00000759 AC XY: 1AN XY: 131702
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1458070Hom.: 0 AF XY: 0.00000276 AC XY: 2AN XY: 724872
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GnomAD4 genome Cov.: 33
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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:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 18, 2023 | This sequence change creates a premature translational stop signal (p.Leu267Glufs*24) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the SURF1 protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of SURF1-related conditions (PMID: 23829769, 24027061). ClinVar contains an entry for this variant (Variation ID: 218303). 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 this premature translational stop signal affects SURF1 function (PMID: 29933018). 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 | research | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift variant c.799_800del (p.Leu267GlufsTer24) in SURF1 gene has been reported in affected individuals in the literature (Echaniz-Laguna A et.al.,2013). This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Leu267GlufsTer24 variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0004106% is reported in gnomAD. This variant causes a frameshift starting with codon Leucine 267, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 24 of the new reading frame, denoted p.Leu267GlufsTer24. 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 . - |
Charcot-Marie-Tooth disease type 4K Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 22, 2013 | - - |
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