1-228166022-T-G

Variant names:

• chr1-228166022-T-G
• rs778284446
• NM_001010867.4:c.206T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001010867.4(IBA57):​c.206T>G​(p.Phe69Cys) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F69S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: IBA57 NM_001010867.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• hereditary spastic paraplegia 74

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IBA57	NM_001010867.4	c.206T>G	p.Phe69Cys	missense_variant	Exon 1 of 3	ENST00000366711.4	NP_001010867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IBA57	ENST00000366711.4	c.206T>G	p.Phe69Cys	missense_variant	Exon 1 of 3	2	NM_001010867.4	ENSP00000355672.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000780 AC: 1 AN: 128172 AF XY: 0.0000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000987 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		1.3
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.83		Gain of catalytic residue at L70 (P = 0.0609);
MVP		0.81
MPC		1.1
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		-0.091	Neutral
Varity_R		0.89
gMVP		0.74
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs778284446; hg19: chr1-228353723;