chr1-228175028-A-G

Variant names:

• chr1-228175028-A-G
• rs876657407
• NM_001010867.4:c.678A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_001010867.4(IBA57):​c.678A>G​(p.Gln226Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000143 in 1,400,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IBA57 NM_001010867.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9369
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.16
• Publications: 3 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 74

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-228175028-A-G is Pathogenic according to our data. Variant chr1-228175028-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 203449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4). . Strength limited to SUPPORTING due to the PP5.

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>G	p.Gln226Gln	splice_region synonymous	Exon 2 of 3	NP_001010867.1	Q5T440
	IBA57	NM_001310327.2		c.99A>G	p.Gln33Gln	splice_region synonymous	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>G	p.Gln226Gln	splice_region synonymous	Exon 2 of 3	ENSP00000355672.3	Q5T440
	IBA57	ENST00000949083.1		c.672A>G	p.Gln224Gln	splice_region synonymous	Exon 2 of 3	ENSP00000619142.1
	IBA57	ENST00000484749.5	TSL:5	n.2678A>G		splice_region non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1400722 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 688596

African (AFR) AF: 0.00 AC: 0 AN: 32170

American (AMR) AF: 0.00 AC: 0 AN: 39408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39096

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 76906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49546

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5474

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078438

Other (OTH) AF: 0.00 AC: 0 AN: 57596

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hereditary spastic paraplegia 74 (3)
1	-	-	Multiple mitochondrial dysfunctions syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		4.2
Mutation Taster		=41/59	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.17		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: rs876657407; hg19: chr1-228362729; COSMIC: COSV100812772;