9-133352138-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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SURF1
NM_003172.4 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.43

Publications

1 publications found
Variant links:
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]
SURF1 Gene-Disease associations (from GenCC):
  • Leigh syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
  • mitochondrial complex IV deficiency, nuclear type 1
    Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
  • Charcot-Marie-Tooth disease type 4K
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
  • Leigh syndrome with cardiomyopathy
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • Leigh syndrome with leukodystrophy
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 9-133352138-GCTCT-G is Pathogenic according to our data. Variant chr9-133352138-GCTCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 2152072.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SURF1NM_003172.4 linkc.752_755delAGAG p.Gln251ProfsTer16 frameshift_variant, splice_region_variant Exon 8 of 9 ENST00000371974.8 NP_003163.1 Q15526-1E5KRX5
SURF1NM_001280787.1 linkc.425_428delAGAG p.Gln142ProfsTer16 frameshift_variant, splice_region_variant Exon 7 of 8 NP_001267716.1 Q15526A0A087WYS9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SURF1ENST00000371974.8 linkc.752_755delAGAG p.Gln251ProfsTer16 frameshift_variant, splice_region_variant Exon 8 of 9 1 NM_003172.4 ENSP00000361042.3 Q15526-1
SURF1ENST00000615505.4 linkc.425_428delAGAG p.Gln142ProfsTer16 frameshift_variant, splice_region_variant Exon 7 of 8 1 ENSP00000482067.1 A0A087WYS9
SURF1ENST00000437995.1 linkn.662_665delAGAG splice_region_variant, non_coding_transcript_exon_variant Exon 7 of 8 5
SURF1ENST00000495952.5 linkn.742_745delAGAG splice_region_variant, non_coding_transcript_exon_variant Exon 4 of 5 2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000454
AC:
1
AN:
220304
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000599
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1445380
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
717382
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33296
American (AMR)
AF:
0.00
AC:
0
AN:
42366
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25746
East Asian (EAS)
AF:
0.0000509
AC:
2
AN:
39270
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83874
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51894
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5716
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1103410
Other (OTH)
AF:
0.00
AC:
0
AN:
59808
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41450
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68038
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Leigh syndrome Pathogenic:1
Mar 20, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
7.4
Mutation Taster
=3/197
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.95
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.95
Position offset: 0
DS_AL_spliceai
0.93
Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs782007828; hg19: chr9-136218993; API