chr1-228166132-A-G

Position:

chr1-228166132-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_001010867.4(IBA57):c.316A>G(p.Thr106Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,521,322 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T106S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000095 ( 0 hom. )

Consequence

IBA57
NM_001010867.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.41

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]

IBA57 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001010867.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-228166132-A-G is Pathogenic according to our data. Variant chr1-228166132-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IBA57	NM_001010867.4 linkuse as main transcript	c.316A>G	p.Thr106Ala	missense_variant	1/3	ENST00000366711.4	NP_001010867.1	Q5T440

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IBA57	ENST00000366711.4 linkuse as main transcript	c.316A>G	p.Thr106Ala	missense_variant	1/3	2	NM_001010867.4	ENSP00000355672.3		Q5T440

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000324

AC:

AN:

123468

Hom.:

AF XY:

0.0000290

AC XY:

AN XY:

68900

show subpopulations

Gnomad AFR exome

AF:

0.000234

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000117

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000415

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000949

AC:

AN:

1369250

Hom.:

Cov.:

AF XY:

0.00000740

AC XY:

AN XY:

675702

show subpopulations

Gnomad4 AFR exome

AF:

0.0000346

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000131

Gnomad4 FIN exome

AF:

0.0000225

Gnomad4 NFE exome

AF:

0.00000936

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 3;C5568837:Hereditary spastic paraplegia 74

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 106 of the IBA57 protein (p.Thr106Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with multiple mitochondrial dysfunctions syndrome 3 (PMID: 27785568, 28671726, 28803783, 34374989). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 545650). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IBA57 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -

Multiple mitochondrial dysfunctions syndrome 3

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PP1,PM3(strong),PM2,PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0065

Eigen

Benign

0.17

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.49

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.5

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.41

Sift

Benign

0.12

Sift4G

Benign

0.23

Polyphen

0.65

Vest4

0.46

MutPred

0.58

Loss of catalytic residue at T106 (P = 0.2172);

MVP

0.79

MPC

0.65

ClinPred

0.32

GERP RS

4.3

Varity_R

0.41

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over