rs73095427

chr1-228174786-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001010867.4(IBA57):c.436C>T(p.Arg146Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IBA57 NM_001010867.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.11

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 1-228174786-C-T is Pathogenic according to our data. Variant chr1-228174786-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545645.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IBA57	NM_001010867.4	c.436C>T	p.Arg146Trp	missense_variant	2/3	ENST00000366711.4
IBA57	NM_001310327.2	c.-144C>T		5_prime_UTR_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IBA57	ENST00000366711.4	c.436C>T	p.Arg146Trp	missense_variant	2/3	2	NM_001010867.4	P1
IBA57	ENST00000484749.5	n.2436C>T		non_coding_transcript_exon_variant	2/3	5
IBA57	ENST00000546123.2	n.156C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458572 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000596 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 2 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 25, 2018

- -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.87		Loss of disorder (P = 0.0638);
MVP		0.73
MPC		0.93
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.93
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs73095427; hg19: chr1-228362487;