1-228166080-C-G

Variant names:

• chr1-228166080-C-G
• rs13375853
• NM_001010867.4:c.264C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001010867.4(IBA57):​c.264C>G​(p.Ala88Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,537,372 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A88A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (44 hom., cov: 34)
  • Exomes 𝑓: 0.0046 (139 hom.)
• Consequence: IBA57 NM_001010867.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.51
• Publications: 1 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-228166080-C-G is Benign according to our data. Variant chr1-228166080-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0781 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IBA57	NM_001010867.4	MANE Select	c.264C>G	p.Ala88Ala	synonymous	Exon 1 of 3	NP_001010867.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IBA57	ENST00000366711.4	TSL:2 MANE Select	c.264C>G	p.Ala88Ala	synonymous	Exon 1 of 3	ENSP00000355672.3

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1635 AN: 152134 Hom.: 44 Cov.: 34

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0846

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0110 AC: 1404 AN: 128192 AF XY: 0.0107

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00475

Gnomad EAS exome AF: 0.0863

Gnomad FIN exome AF: 0.00483

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00682

GnomAD4 exome AF: 0.00456 AC: 6319 AN: 1385130 Hom.: 139 Cov.: 33 AF XY: 0.00473 AC XY: 3236 AN XY: 683638

African (AFR) AF: 0.0235 AC: 707 AN: 30110

American (AMR) AF: 0.00182 AC: 64 AN: 35162

Ashkenazi Jewish (ASJ) AF: 0.00363 AC: 90 AN: 24826

East Asian (EAS) AF: 0.0785 AC: 2740 AN: 34914

South Asian (SAS) AF: 0.0127 AC: 990 AN: 77844

European-Finnish (FIN) AF: 0.00424 AC: 179 AN: 42246

Middle Eastern (MID) AF: 0.00389 AC: 22 AN: 5662

European-Non Finnish (NFE) AF: 0.000972 AC: 1047 AN: 1076702

Other (OTH) AF: 0.00832 AC: 480 AN: 57664

GnomAD4 genome AF: 0.0107 AC: 1634 AN: 152242 Hom.: 44 Cov.: 34 AF XY: 0.0109 AC XY: 814 AN XY: 74458

African (AFR) AF: 0.0222 AC: 921 AN: 41516

American (AMR) AF: 0.00320 AC: 49 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.0847 AC: 439 AN: 5184

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4828

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68004

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00146 Hom.: 1

Bravo AF: 0.0113

Asia WGS AF: 0.0330 AC: 115 AN: 3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 15, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Multiple mitochondrial dysfunctions syndrome 3;C5568837:Hereditary spastic paraplegia 74 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.5
DANN	Benign	0.59
PhyloP100		-2.5
PromoterAI		0.0047	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs13375853; hg19: chr1-228353781;