rs730882246
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The ENST00000556816.6(ISCA2):c.229G>A(p.Gly77Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
ISCA2
ENST00000556816.6 missense
ENST00000556816.6 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 9.64
Genes affected
ISCA2 (HGNC:19857): (iron-sulfur cluster assembly 2) The protein encoded by this gene is an A-type iron-sulfur cluster (ISC) protein found in mitochondria. The encoded protein appears to be involved in the maturation of mitochondrial iron-sulfur proteins. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.866
PP5
Variant 14-74494329-G-A is Pathogenic according to our data. Variant chr14-74494329-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74494329-G-A is described in Lovd as [Pathogenic]. Variant chr14-74494329-G-A is described in Lovd as [Likely_pathogenic]. Variant chr14-74494329-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ISCA2 | NM_194279.4 | c.229G>A | p.Gly77Ser | missense_variant | 3/4 | ENST00000556816.6 | NP_919255.2 | |
ISCA2 | NM_001272007.2 | c.174+177G>A | intron_variant | NP_001258936.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ISCA2 | ENST00000556816.6 | c.229G>A | p.Gly77Ser | missense_variant | 3/4 | 1 | NM_194279.4 | ENSP00000452007 | P1 | |
ISCA2 | ENST00000298818.12 | c.229G>A | p.Gly77Ser | missense_variant | 3/4 | 5 | ENSP00000298818 | |||
ISCA2 | ENST00000554924.1 | c.174+177G>A | intron_variant | 2 | ENSP00000450523 | |||||
ISCA2 | ENST00000555139.1 | n.232G>A | non_coding_transcript_exon_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461860Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727230
GnomAD4 exome
AF:
AC:
2
AN:
1461860
Hom.:
Cov.:
31
AF XY:
AC XY:
2
AN XY:
727230
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Multiple mitochondrial dysfunctions syndrome 4 Pathogenic:8Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 15, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Nov 08, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | May 01, 2016 | Our laboratory reported two molecular diagnoses in TUBB3 (NM_006086.3:c.982G>A) and ISCA2 (NM_194279.3:c.229G>A) in an individual with delayed motor milestones, developmental regression, hypotonia, hypertonia in extremities, increased reflexes with sustained ankle clonus bilaterally, macrocephaly, poor visual response withoptic nerve pallor, and brain imaging demonstrating demyelination and white matter disease. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 14, 2023 | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | May 08, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 28, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ISCA2 function (PMID: 29297947). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 77 of the ISCA2 protein (p.Gly77Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple mitochondrial dysfunctions syndrome (PMID: 25558065, 29122497, 29297947). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183353). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 07, 2020 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29122497, 25558065, 25539947, 27959697, 29019354, 29297947, 30202406, 31130284, 32552793, 32342562) - |
Fatal multiple mitochondrial dysfunctions syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | The c.229G>A (p.Gly77Ser) variant has been reported in two studies in a total of five multiple mitochondrial dysfunctions syndrome patients from three families, all of whom were found to be homozygous for the variant (Alazami et al. 2015; Al-Hassnan et al. 2015). The p.Gly77Ser variant was shown to segregate with disease across two generations in all three families and to be the result of a founder effect. The variant was absent from 1,060 ethnically matched controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The Gly77 residue is highly conserved over 58 different species. Functional studies demonstrated that the p.Gly77Ser variant had only 20% of normal complex I activity and resulted in a significant depletion of mitochondrial DNA copy number in patient fibroblasts. Modelling studies showed that the p.Gly77Ser variant occurs in a loop that is directly involved in iron-sulphur cluster binding. Substitution of the glycine by serine is predicted to affect the stability of the flexibility of the loop and therefore the efficiency of binding to the iron-sulphur cluster (Alazami et al. 2015; Al-Hassnan et al. 2015). Based on the evidence, the p.Gly77Ser variant is classified as likely pathogenic for multiple mitochondrial dysfunctions syndrome. - |
Optic atrophy;C0426970:Spastic tetraplegia;C0557874:Global developmental delay;C1853743:Axial hypotonia;C1858430:Death in infancy;C2315100:Failure to thrive;CN228271:High CSF lactic acid;CN228311:Neurodegeration Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Dec 01, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of catalytic residue at G78 (P = 6e-04);Gain of catalytic residue at G78 (P = 6e-04);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at