chr9-133352138-GCTCT-G
Variant summary
Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1PM2PP3_ModeratePP5_Moderate
The NM_003172.4(SURF1):c.752_755delAGAG(p.Gln251ProfsTer16) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,597,584 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q251Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_003172.4 frameshift, splice_region
Scores
Clinical Significance
Conservation
Publications
- Leigh syndromeInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
- mitochondrial complex IV deficiency, nuclear type 1Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
- Charcot-Marie-Tooth disease type 4KInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
- Leigh syndrome with cardiomyopathyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Leigh syndrome with leukodystrophyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SURF1 | NM_003172.4 | c.752_755delAGAG | p.Gln251ProfsTer16 | frameshift_variant, splice_region_variant | Exon 8 of 9 | ENST00000371974.8 | NP_003163.1 | |
SURF1 | NM_001280787.1 | c.425_428delAGAG | p.Gln142ProfsTer16 | frameshift_variant, splice_region_variant | Exon 7 of 8 | NP_001267716.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SURF1 | ENST00000371974.8 | c.752_755delAGAG | p.Gln251ProfsTer16 | frameshift_variant, splice_region_variant | Exon 8 of 9 | 1 | NM_003172.4 | ENSP00000361042.3 | ||
SURF1 | ENST00000615505.4 | c.425_428delAGAG | p.Gln142ProfsTer16 | frameshift_variant, splice_region_variant | Exon 7 of 8 | 1 | ENSP00000482067.1 | |||
SURF1 | ENST00000437995.1 | n.662_665delAGAG | splice_region_variant, non_coding_transcript_exon_variant | Exon 7 of 8 | 5 | |||||
SURF1 | ENST00000495952.5 | n.742_745delAGAG | splice_region_variant, non_coding_transcript_exon_variant | Exon 4 of 5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00000454 AC: 1AN: 220304 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1445380Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 717382 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74338 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Leigh syndrome Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gln251Profs*16) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 50 amino acid(s) of the SURF1 protein. This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Leigh syndrome (PMID: 22410471, 28639102, 29933018, 33013660). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at