chr1-228166102-T-C

Variant names:

• chr1-228166102-T-C
• rs765926471
• NM_001010867.4:c.286T>C

Variant summary

Our verdict is Pathogenic. The variant received 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y96C) has been classified as Uncertain significance.

• 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:4
• Conservation: PhyloP100: 2.87
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• multiple mitochondrial dysfunctions syndrome 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• hereditary spastic paraplegia 74

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 545649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IBA57	NM_001010867.4	c.286T>C	p.Tyr96His	missense_variant	Exon 1 of 3	ENST00000366711.4	NP_001010867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IBA57	ENST00000366711.4	c.286T>C	p.Tyr96His	missense_variant	Exon 1 of 3	2	NM_001010867.4	ENSP00000355672.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 129534 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29938

American (AMR) AF: 0.00 AC: 0 AN: 34716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24698

East Asian (EAS) AF: 0.00 AC: 0 AN: 34932

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00000279 AC: 3 AN: 1076512

Other (OTH) AF: 0.00 AC: 0 AN: 57644

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00295270), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000944 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 3 Pathogenic:3

-

Molecular Diagnostic Laboratory, Beijing Chigene Translational Medicine Research Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 01, 2019

The Molecular Genetic and Pathologic Diagnosis Center of Neuromuscular Disorder, Children's Hospital of Fudan University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Multiple mitochondrial dysfunctions syndrome 3;C5568837:Hereditary spastic paraplegia 74 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PM3_VeryStrong -

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
PhyloP100		2.9
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
PromoterAI		-0.21	Neutral
Varity_R		0.91
gMVP		0.77
Mutation Taster		=39/61	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs765926471; hg19: chr1-228353803;