17-10681157-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_004589.4(SCO1):ā€‹c.868A>Gā€‹(p.Ile290Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000782 in 1,614,190 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00062 ( 0 hom., cov: 33)
Exomes š‘“: 0.00080 ( 3 hom. )

Consequence

SCO1
NM_004589.4 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 1.64
Variant links:
Genes affected
SCO1 (HGNC:10603): (synthesis of cytochrome C oxidase 1) Mammalian cytochrome c oxidase (COX) catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. In yeast, 2 related COX assembly genes, SCO1 and SCO2 (synthesis of cytochrome c oxidase), enable subunits 1 and 2 to be incorporated into the holoprotein. This gene is the human homolog to the yeast SCO1 gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.011493444).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000617 (94/152314) while in subpopulation SAS AF= 0.00228 (11/4830). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCO1NM_004589.4 linkc.868A>G p.Ile290Val missense_variant Exon 6 of 6 ENST00000255390.10 NP_004580.1 O75880

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCO1ENST00000255390.10 linkc.868A>G p.Ile290Val missense_variant Exon 6 of 6 1 NM_004589.4 ENSP00000255390.5 O75880

Frequencies

GnomAD3 genomes
AF:
0.000618
AC:
94
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00228
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000750
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000620
AC:
156
AN:
251478
Hom.:
0
AF XY:
0.000758
AC XY:
103
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00245
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000607
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000799
AC:
1168
AN:
1461876
Hom.:
3
Cov.:
31
AF XY:
0.000847
AC XY:
616
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.000448
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00301
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000746
Gnomad4 OTH exome
AF:
0.00101
GnomAD4 genome
AF:
0.000617
AC:
94
AN:
152314
Hom.:
0
Cov.:
33
AF XY:
0.000564
AC XY:
42
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.000722
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00228
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000750
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000654
Hom.:
0
Bravo
AF:
0.000593
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000814
AC:
7
ExAC
AF:
0.000610
AC:
74
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000545
EpiControl
AF:
0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Nov 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 26, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS1 -

Sep 11, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Mitochondrial complex 4 deficiency, nuclear type 4 Uncertain:2
Apr 14, 2022
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 02, 2020
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mitochondrial complex IV deficiency, nuclear type 1 Uncertain:2
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Leigh syndrome Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
T;T
Eigen
Benign
0.073
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.69
T;T
M_CAP
Benign
0.041
D
MetaRNN
Benign
0.011
T;T
MetaSVM
Uncertain
0.17
D
MutationAssessor
Benign
1.9
L;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.77
N;.
REVEL
Uncertain
0.34
Sift
Benign
0.13
T;.
Sift4G
Benign
0.41
T;T
Polyphen
0.056
B;.
Vest4
0.27
MVP
0.57
MPC
0.12
ClinPred
0.049
T
GERP RS
5.7
Varity_R
0.17
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs139771078; hg19: chr17-10584474; API