1-228165898-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001010867.4(IBA57):​c.82A>G​(p.Arg28Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000302 in 1,256,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R28R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

IBA57
NM_001010867.4 missense

Scores

2
1
16

Clinical Significance

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

Conservation

PhyloP100: 1.15
Variant links:
Genes affected
IBA57 (HGNC:27302): (iron-sulfur cluster assembly factor IBA57) The protein encoded by this gene localizes to the mitochondrion and is part of the iron-sulfur cluster assembly pathway. The encoded protein functions late in the biosynthesis of mitochondrial 4Fe-4S proteins. Defects in this gene have been associated with autosomal recessive spastic paraplegia-74 and with multiple mitochondrial dysfunctions syndrome-3. Two transcript variants encoding different isoforms have been found for this gene. The smaller isoform is not likely to be localized to the mitochondrion since it lacks the amino-terminal transit peptide. [provided by RefSeq, Jul 2015]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16893956).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IBA57NM_001010867.4 linkc.82A>G p.Arg28Gly missense_variant Exon 1 of 3 ENST00000366711.4 NP_001010867.1 Q5T440

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IBA57ENST00000366711.4 linkc.82A>G p.Arg28Gly missense_variant Exon 1 of 3 2 NM_001010867.4 ENSP00000355672.3 Q5T440

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000302
AC:
38
AN:
1256790
Hom.:
0
Cov.:
30
AF XY:
0.0000340
AC XY:
21
AN XY:
616750
show subpopulations
Gnomad4 AFR exome
AF:
0.0000398
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:
0.0000334
Gnomad4 OTH exome
AF:
0.0000581
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 3;C5568837:Hereditary spastic paraplegia 74 Uncertain:1
Aug 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 28 of the IBA57 protein (p.Arg28Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IBA57-related conditions. ClinVar contains an entry for this variant (Variation ID: 1946523). 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 tolerated. 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
Mar 21, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.82A>G (p.R28G) alteration is located in exon 1 (coding exon 1) of the IBA57 gene. This alteration results from a A to G substitution at nucleotide position 82, causing the arginine (R) at amino acid position 28 to be replaced by a glycine (G). 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
0.063
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
16
DANN
Benign
0.81
DEOGEN2
Benign
0.0057
T
Eigen
Benign
-0.80
Eigen_PC
Benign
-0.78
FATHMM_MKL
Benign
0.075
N
LIST_S2
Benign
0.52
T
M_CAP
Pathogenic
0.37
D
MetaRNN
Benign
0.17
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-1.5
N
REVEL
Benign
0.034
Sift
Benign
0.043
D
Sift4G
Uncertain
0.032
D
Polyphen
0.0020
B
Vest4
0.42
MutPred
0.32
Loss of methylation at R28 (P = 0.013);
MVP
0.24
MPC
0.33
ClinPred
0.16
T
GERP RS
2.6
Varity_R
0.093
gMVP
0.49

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: rs1263563131; hg19: chr1-228353599; API