rs1053773776

chr1-228166132-A-Gchr1-228166132-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.41

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]

ACMG classification

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, 5 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	UniProt
IBA57	NM_001010867.4	c.316A>G	p.Thr106Ala	missense_variant	1/3	ENST00000366711.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IBA57	ENST00000366711.4	c.316A>G	p.Thr106Ala	missense_variant	1/3	2	NM_001010867.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152072 Hom.: 0 Cov.: 34

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: 4 AN: 123468 Hom.: 0 AF XY: 0.0000290 AC XY: 2 AN XY: 68900

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: 13 AN: 1369250 Hom.: 0 Cov.: 33 AF XY: 0.00000740 AC XY: 5 AN XY: 675702

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: 3 AN: 152072 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74282

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 3;C5568837:Hereditary spastic paraplegia 74 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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:1

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	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	26
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0065	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.92	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.41
Sift	Benign	0.12	T
Sift4G	Benign	0.23	T
Polyphen		0.65	P
Vest4		0.46
MutPred		0.58		Loss of catalytic residue at T106 (P = 0.2172);
MVP		0.79
MPC		0.65
ClinPred		0.32	T
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

Other links and lift over

dbSNP: rs1053773776; hg19: chr1-228353833;