1-228166132-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.41

Publications

5 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: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 545650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010867.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IBA57	NM_001010867.4	MANE Select	c.316A>G	p.Thr106Ala	missense	Exon 1 of 3	NP_001010867.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IBA57	ENST00000366711.4	TSL:2 MANE Select	c.316A>G	p.Thr106Ala	missense	Exon 1 of 3	ENSP00000355672.3
	IBA57	ENST00000949083.1		c.316A>G	p.Thr106Ala	missense	Exon 1 of 3	ENSP00000619142.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000324

AC:

AN:

123468

AF XY:

0.0000290

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000415

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000949

AC:

AN:

1369250

Hom.:

Cov.:

AF XY:

0.00000740

AC XY:

AN XY:

675702

show subpopulations

African (AFR)

AF:

0.0000346

AC:

AN:

28938

American (AMR)

AF:

0.00

AC:

AN:

31668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23828

East Asian (EAS)

AF:

0.00

AC:

AN:

33686

South Asian (SAS)

AF:

0.0000131

AC:

AN:

76388

European-Finnish (FIN)

AF:

0.0000225

AC:

AN:

44502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

0.00000936

AC:

AN:

1067976

Other (OTH)

AF:

0.00

AC:

AN:

56710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74282

show subpopulations

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

African (AFR)

AF:

0.0000724

AC:

AN:

41408

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00400497), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Multiple mitochondrial dysfunctions syndrome 3 (2)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0065

Eigen

Benign

0.17

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.49

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.5

PhyloP100

2.4

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.41

Sift

Benign

0.12

Sift4G

Benign

0.23

Polyphen

0.65

Vest4

0.46

MutPred

0.58

Loss of catalytic residue at T106 (P = 0.2172)

MVP

0.79

MPC

0.65

ClinPred

0.32

GERP RS

4.3

PromoterAI

-0.082

Neutral

(source)

Varity_R

0.41

gMVP

0.47

Mutation Taster

=14/86

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over