rs775646159

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001010867.4(IBA57):​c.335T>A​(p.Leu112Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 34)

Consequence

IBA57
NM_001010867.4 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.51
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-228166151-T-A is Pathogenic according to our data. Variant chr1-228166151-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1396845.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IBA57NM_001010867.4 linkuse as main transcriptc.335T>A p.Leu112Ter stop_gained 1/3 ENST00000366711.4 NP_001010867.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IBA57ENST00000366711.4 linkuse as main transcriptc.335T>A p.Leu112Ter stop_gained 1/32 NM_001010867.4 ENSP00000355672 P1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 3;C5568837:Hereditary spastic paraplegia 74 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 08, 2024This sequence change creates a premature translational stop signal (p.Leu112*) in the IBA57 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IBA57 are known to be pathogenic (PMID: 23462291, 25971455, 27785568, 28671726). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IBA57-related conditions. ClinVar contains an entry for this variant (Variation ID: 1396845). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
36
DANN
Benign
0.96
Eigen
Uncertain
0.33
Eigen_PC
Benign
0.059
FATHMM_MKL
Benign
0.097
N
MutationTaster
Benign
1.0
A
Vest4
0.11
GERP RS
4.3

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.22
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.22
Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-228353852; API