chr1-228166102-T-C

Position:

• chr1-228166102-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001010867.4(IBA57):​c.286T>C​(p.Tyr96His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000289 in 1,385,786 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: IBA57 NM_001010867.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.87

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 1-228166102-T-C is Pathogenic according to our data. Variant chr1-228166102-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 545649.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	c.286T>C	p.Tyr96His	missense_variant	1/3	ENST00000366711.4	NP_001010867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IBA57	ENST00000366711.4	c.286T>C	p.Tyr96His	missense_variant	1/3	2	NM_001010867.4	ENSP00000355672	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1385786 Hom.: 0 Cov.: 33 AF XY: 0.00000146 AC XY: 1 AN XY: 684042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ExAC AF: 0.00000944 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 3 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	The Molecular Genetic and Pathologic Diagnosis Center of Neuromuscular Disorder, Children's Hospital of Fudan University	Dec 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory, Beijing Chigene Translational Medicine Research Center	-	Through Trio-WES, compound heterozygous variants in the IBA57 gene were identified in the proband's testing data, which are [c.286T>C/p.Y96H] and [c.754G>A/p.G252S]. The c.286T>C variant is predicted to result in the substitution of the 96th amino acid in the protein from Tyrosine (Tyr) to Histidine (His), inherited from the father. The c.754G>A variant is predicted to result in the substitution of the 252nd amino acid in the protein from Glycine (Gly) to Serine (Ser), inherited from the mother. The c.286T>C variant has the rs number rs765926471 and is not recorded in general population carrier frequency databases such as the Thousand Genomes Project or gnomAD. According to the ACMG guidelines, this variant is classified as a pathogenic variant: PM2_Supporting + PM3_VeryStrong + PP1_Moderate + PP3, with the specific basis as follows: PM3_VeryStrong：The variant has been detected as a homozygous variant or in trans phase with pathogenic (P) or likely pathogenic (LP) variants, or in trans phase with variants of uncertain significance (VUS) in one or more patients with a phenotype correlation, achieving a PM3-Case_Score of ≥4.0 [PMID: 28671726, 32348839]. PP1_Moderate：The variant has been found to co-segregate at least twice in the self-check case database and literature reports for recessive diseases or at least four times for dominant diseases [PMID: 28671726]. PP3：Various bioinformatics computational methods predict that the variant has a deleterious effect on the gene/gene product or affects splicing to a level that meets the supportive threshold. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.85		Gain of disorder (P = 0.0268);
MVP		0.84
MPC		1.0
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.91
gMVP		0.77

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: rs765926471; hg19: chr1-228353803;