1-228175028-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate 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

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 Uncertain_significance. Variant got 3 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 id is 203449.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IBA57	NM_001010867.4	c.678A>G	p.Gln226Gln	splice_region_variant, synonymous_variant	Exon 2 of 3	ENST00000366711.4	NP_001010867.1
IBA57	NM_001310327.2	c.99A>G	p.Gln33Gln	splice_region_variant, synonymous_variant	Exon 2 of 3		NP_001297256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IBA57	ENST00000366711.4	c.678A>G	p.Gln226Gln	splice_region_variant, synonymous_variant	Exon 2 of 3	2	NM_001010867.4	ENSP00000355672.3
IBA57	ENST00000484749.5	n.2678A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	5
IBA57	ENST00000546123.2	n.398A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	2

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

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: 0.0000130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 74 Pathogenic:3

Feb 17, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 24, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Synonymous variant near exon/intron junction previously reported to alter splicing and result in a loss of normal protein function through nonsense-mediated decay (NMD) or protein truncation (PMID: 25609768). Althogh SpliceAI score is low at 0.17 (>=0.2, moderate evidence for spliceogenicity), abnormal splicing has been reported (PMID: 25609768). Functional studies also provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 25609768). Synonymous variant near exon/intron junction previously reported to alter splicing and result in a loss of normal protein function through nonsense-mediated decay (NMD) or protein truncation (PMID: 25609768). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 22, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was previously reported in 11 affected subjects of a highly consanguineous 5-generation family of Arab origin. The affected individuals in this family manifested with very slowly progressive, childhood-onset gait impairment, knee hyperreflexia and with a combination of spastic paraplegia, optic atrophy, and peripheral neuropathy (SPOAN). This variant was reported to segregate in an autosomal recessive pattern in affected members [PMID: 25609768]. In-vitro functional analysis using cDNA from both fresh lymphocytes and transformed lymphoblastoid cells from a patient harboring c.678A>G variant revealed a severely decreased amount of normal IBA57 protein and an aberrantly spliced messenger RNA with a premature stop codon. In addition, decreased functional IBA57 protein demonstrated reduced levels and activities of several mitochondrial [4Fe-4S] proteins in complexes I and II suggesting its loss-of-function [PMID: 25609768]. -

Multiple mitochondrial dysfunctions syndrome 3 Pathogenic:1

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657407; hg19: chr1-228362729; COSMIC: COSV100812772;