GeneBe

9-133352452-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_003172.4(SURF1):​c.745A>C​(p.Asn249His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N249D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SURF1
NM_003172.4 missense

Scores

5
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.46

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: -0.68006 (below the threshold of 3.09). Trascript score misZ: -1.3185 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome with leukodystrophy, Leigh syndrome, mitochondrial complex IV deficiency, nuclear type 1, Charcot-Marie-Tooth disease type 4K, Leigh syndrome with cardiomyopathy.
BP4
Computational evidence support a benign effect (MetaRNN=0.3717828).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SURF1NM_003172.4 linkc.745A>C p.Asn249His missense_variant Exon 7 of 9 ENST00000371974.8 NP_003163.1 Q15526-1E5KRX5
SURF1NM_001280787.1 linkc.418A>C p.Asn140His missense_variant Exon 6 of 8 NP_001267716.1 Q15526A0A087WYS9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SURF1ENST00000371974.8 linkc.745A>C p.Asn249His missense_variant Exon 7 of 9 1 NM_003172.4 ENSP00000361042.3 Q15526-1
SURF1ENST00000615505.4 linkc.418A>C p.Asn140His missense_variant Exon 6 of 8 1 ENSP00000482067.1 A0A087WYS9
SURF1ENST00000437995.1 linkn.655A>C non_coding_transcript_exon_variant Exon 6 of 8 5
SURF1ENST00000495952.5 linkn.735A>C non_coding_transcript_exon_variant Exon 3 of 5 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461882
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727238
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53410
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112012
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.023
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
17
DANN
Benign
0.90
DEOGEN2
Uncertain
0.75
D;.
Eigen
Benign
-0.61
Eigen_PC
Benign
-0.59
FATHMM_MKL
Uncertain
0.97
D
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.37
T;T
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Benign
1.5
L;.
PhyloP100
3.5
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.7
N;.
REVEL
Benign
0.26
Sift
Benign
0.046
D;.
Sift4G
Benign
0.57
T;T
Polyphen
0.30
B;.
Vest4
0.36
MutPred
0.54
Loss of stability (P = 0.0248);.;
MVP
0.78
MPC
0.088
ClinPred
0.58
D
GERP RS
0.76
Varity_R
0.081
gMVP
0.68
Mutation Taster
=87/13
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs587669420; hg19: chr9-136219307; API