rs781831910

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The ENST00000371974.8(SURF1):​c.118A>T​(p.Arg40Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SURF1
ENST00000371974.8 missense

Scores

9
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.180
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a chain Surfeit locus protein 1 (size 299) in uniprot entity SURF1_HUMAN there are 49 pathogenic changes around while only 10 benign (83%) in ENST00000371974.8
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.4089968).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SURF1NM_003172.4 linkuse as main transcriptc.118A>T p.Arg40Trp missense_variant 3/9 ENST00000371974.8 NP_003163.1
SURF1NM_001280787.1 linkuse as main transcriptc.-210A>T 5_prime_UTR_variant 2/8 NP_001267716.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SURF1ENST00000371974.8 linkuse as main transcriptc.118A>T p.Arg40Trp missense_variant 3/91 NM_003172.4 ENSP00000361042 P1Q15526-1
SURF1ENST00000615505.4 linkuse as main transcriptc.-210A>T 5_prime_UTR_variant 2/81 ENSP00000482067
SURF1ENST00000437995.1 linkuse as main transcriptn.64A>T non_coding_transcript_exon_variant 2/85

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251040
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461190
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
726874
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Leigh syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 23, 2022This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 40 of the SURF1 protein (p.Arg40Trp). This variant is present in population databases (rs781831910, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SURF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 456663). 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: "Benign"; 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. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 30, 2023The c.118A>T (p.R40W) alteration is located in exon 3 (coding exon 3) of the SURF1 gene. This alteration results from a A to T substitution at nucleotide position 118, causing the arginine (R) at amino acid position 40 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Uncertain
0.080
D
BayesDel_noAF
Benign
-0.12
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.26
FATHMM_MKL
Benign
0.26
N
M_CAP
Uncertain
0.24
D
MetaRNN
Benign
0.41
T
MetaSVM
Uncertain
-0.16
T
MutationAssessor
Benign
1.9
L
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-2.2
N
REVEL
Uncertain
0.40
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0060
D
Polyphen
0.89
P
Vest4
0.42
MVP
0.81
MPC
0.025
ClinPred
0.28
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.090
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs781831910; hg19: chr9-136221801; API