IBA57 p.Gln226His

Variant names:

• chr1-228175028-A-T
• NM_001010867.4:c.678A>T
• IBA57 p.Gln226His

Your query was ambiguous. Multiple possible variants found:

• chr1-228175028-A-T
• chr1-228175028-A-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001010867.4(IBA57):​c.678A>T​(p.Gln226His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q226Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IBA57 NM_001010867.4 missense, splice_region
• Scores: Splicing: ADA: 0.9967
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.16
• Publications: 0 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 74

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.678A>T	p.Gln226His	missense splice_region	Exon 2 of 3	NP_001010867.1	Q5T440
	IBA57	NM_001310327.2		c.99A>T	p.Gln33His	missense splice_region	Exon 2 of 3	NP_001297256.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IBA57	ENST00000366711.4	TSL:2 MANE Select	c.678A>T	p.Gln226His	missense splice_region	Exon 2 of 3	ENSP00000355672.3	Q5T440
	IBA57	ENST00000949083.1		c.672A>T	p.Gln224His	missense splice_region	Exon 2 of 3	ENSP00000619142.1
	IBA57	ENST00000484749.5	TSL:5	n.2678A>T		splice_region non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.14
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.59	N
PhyloP100		4.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.080
Sift	Benign	0.19	T
Sift4G	Benign	0.56	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.83
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-228362729;