rs1554768246
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003172.4(SURF1):c.759_760insA(p.Val254SerfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T253T) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
SURF1
NM_003172.4 frameshift
NM_003172.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.691
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 12 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 34 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 9-133352134-C-CT is Pathogenic according to our data. Variant chr9-133352134-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 456666.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SURF1 | NM_003172.4 | c.759_760insA | p.Val254SerfsTer38 | frameshift_variant | 8/9 | ENST00000371974.8 | |
SURF1 | NM_001280787.1 | c.432_433insA | p.Val145SerfsTer38 | frameshift_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SURF1 | ENST00000371974.8 | c.759_760insA | p.Val254SerfsTer38 | frameshift_variant | 8/9 | 1 | NM_003172.4 | P1 | |
SURF1 | ENST00000615505.4 | c.432_433insA | p.Val145SerfsTer38 | frameshift_variant | 7/8 | 1 | |||
SURF1 | ENST00000437995.1 | n.669_670insA | non_coding_transcript_exon_variant | 7/8 | 5 | ||||
SURF1 | ENST00000495952.5 | n.749_750insA | non_coding_transcript_exon_variant | 4/5 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Leigh syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 14, 2021 | - - |
Computational scores
Source:
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Calibrated prediction
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Prediction
Splicing
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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