9-133351951-A-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_003172.4(SURF1):c.865T>G(p.Trp289Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,836 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
SURF1
NM_003172.4 missense
NM_003172.4 missense
Scores
12
4
2
Clinical Significance
Conservation
PhyloP100: 6.66
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a transmembrane_region Helical (size 16) in uniprot entity SURF1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003172.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.989
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SURF1 | NM_003172.4 | c.865T>G | p.Trp289Gly | missense_variant | 9/9 | ENST00000371974.8 | |
SURF1 | NM_001280787.1 | c.538T>G | p.Trp180Gly | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SURF1 | ENST00000371974.8 | c.865T>G | p.Trp289Gly | missense_variant | 9/9 | 1 | NM_003172.4 | P1 | |
SURF1 | ENST00000615505.4 | c.538T>G | p.Trp180Gly | missense_variant | 8/8 | 1 | |||
SURF1 | ENST00000437995.1 | n.775T>G | non_coding_transcript_exon_variant | 8/8 | 5 | ||||
SURF1 | ENST00000495952.5 | n.855T>G | non_coding_transcript_exon_variant | 5/5 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250806Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135670
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461622Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727068
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74358
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Leigh syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 14, 2021 | This sequence change replaces tryptophan with glycine at codon 289 of the SURF1 protein (p.Trp289Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. This variant is present in population databases (rs373591762, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with SURF1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Benign
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;D
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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