1-228174995-C-G

Variant names:

• chr1-228174995-C-G
• NM_001010867.4:c.645C>G
• IBA57 p.Asp215Glu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001010867.4(IBA57):​c.645C>G​(p.Asp215Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D215D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IBA57 NM_001010867.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0850
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary spastic paraplegia 74

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11950812).

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.645C>G	p.Asp215Glu	missense	Exon 2 of 3	NP_001010867.1	Q5T440
	IBA57	NM_001310327.2		c.66C>G	p.Asp22Glu	missense	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.645C>G	p.Asp215Glu	missense	Exon 2 of 3	ENSP00000355672.3	Q5T440
	IBA57	ENST00000949083.1		c.639C>G	p.Asp213Glu	missense	Exon 2 of 3	ENSP00000619142.1
	IBA57	ENST00000484749.5	TSL:5	n.2645C>G		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	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.2
DANN	Benign	0.94
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.085
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.059
Sift	Benign	0.030	D
Sift4G	Benign	0.064	T
Varity_R		0.17
gMVP		0.64
Mutation Taster		=93/7	polymorphism

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

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

Other links and lift over

hg19: chr1-228362696;