rs1553264725

chr1-228175128-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001010867.4(IBA57):c.686C>T(p.Pro229Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,620 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IBA57 NM_001010867.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.68

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873
• PP5: Variant 1-228175128-C-T is Pathogenic according to our data. Variant chr1-228175128-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 545647.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IBA57	NM_001010867.4	c.686C>T	p.Pro229Leu	missense_variant	3/3	ENST00000366711.4
IBA57	NM_001310327.2	c.107C>T	p.Pro36Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IBA57	ENST00000366711.4	c.686C>T	p.Pro229Leu	missense_variant	3/3	2	NM_001010867.4	P1
IBA57	ENST00000484749.5	n.2686C>T		non_coding_transcript_exon_variant	3/3	5
IBA57	ENST00000546123.2	n.406C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459620 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725992

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.014	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.016	D
Sift4G	Benign	0.097	T
Polyphen		0.99	D
Vest4		0.65
MutPred		0.74		Loss of disorder (P = 0.0348);
MVP		0.78
MPC		0.74
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.70
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1553264725; hg19: chr1-228362829;