1-228175028-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_001010867.4(IBA57):c.678A>G(p.Gln226Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000143 in 1,400,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

IBA57
NM_001010867.4 splice_region, synonymous

Scores

Splicing: ADA: 0.9369

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.16

Publications

3 publications found

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 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

IBA57 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-228175028-A-G is Pathogenic according to our data. Variant chr1-228175028-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 203449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IBA57	NM_001010867.4 link	c.678A>G	p.Gln226Gln	splice_region_variant, synonymous_variant	Exon 2 of 3	ENST00000366711.4	NP_001010867.1	Q5T440
IBA57	NM_001310327.2 link	c.99A>G	p.Gln33Gln	splice_region_variant, synonymous_variant	Exon 2 of 3		NP_001297256.1	B4E1G9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IBA57	ENST00000366711.4 link	c.678A>G	p.Gln226Gln	splice_region_variant, synonymous_variant	Exon 2 of 3	2	NM_001010867.4	ENSP00000355672.3	Q5T440
IBA57	ENST00000484749.5 link	n.2678A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	5
IBA57	ENST00000546123.2 link	n.398A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1400722

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

688596

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32170

American (AMR)

AF:

0.00

AC:

AN:

39408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22088

East Asian (EAS)

AF:

0.00

AC:

AN:

39096

South Asian (SAS)

AF:

0.0000130

AC:

AN:

76906

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49546

Middle Eastern (MID)

AF:

0.000183

AC:

AN:

5474

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078438

Other (OTH)

AF:

0.00

AC:

AN:

57596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 74

Pathogenic:3

May 22, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was previously reported in 11 affected subjects of a highly consanguineous 5-generation family of Arab origin. The affected individuals in this family manifested with very slowly progressive, childhood-onset gait impairment, knee hyperreflexia and with a combination of spastic paraplegia, optic atrophy, and peripheral neuropathy (SPOAN). This variant was reported to segregate in an autosomal recessive pattern in affected members [PMID: 25609768]. In-vitro functional analysis using cDNA from both fresh lymphocytes and transformed lymphoblastoid cells from a patient harboring c.678A>G variant revealed a severely decreased amount of normal IBA57 protein and an aberrantly spliced messenger RNA with a premature stop codon. In addition, decreased functional IBA57 protein demonstrated reduced levels and activities of several mitochondrial [4Fe-4S] proteins in complexes I and II suggesting its loss-of-function [PMID: 25609768]. -

Feb 17, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 24, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Synonymous variant near exon/intron junction previously reported to alter splicing and result in a loss of normal protein function through nonsense-mediated decay (NMD) or protein truncation (PMID: 25609768). Althogh SpliceAI score is low at 0.17 (>=0.2, moderate evidence for spliceogenicity), abnormal splicing has been reported (PMID: 25609768). Functional studies also provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 25609768). Synonymous variant near exon/intron junction previously reported to alter splicing and result in a loss of normal protein function through nonsense-mediated decay (NMD) or protein truncation (PMID: 25609768). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Multiple mitochondrial dysfunctions syndrome 3

Pathogenic:1

Jun 01, 2022

Solve-RD Consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

4.2

Mutation Taster

=41/59

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Benign

0.71

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over