rs765132163

Variant names:

• chr1-228165966-C-A
• rs765132163
• NM_001010867.4:c.150C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-228165966-C-A
• chr1-228165966-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001010867.4(IBA57):​c.150C>A​(p.Cys50*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. C50C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IBA57 NM_001010867.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.891
• 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: 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-228165966-C-A is Pathogenic according to our data. Variant chr1-228165966-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 545654.Status of the report is no_assertion_criteria_provided, 0 stars.

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.150C>A	p.Cys50*	stop_gained	Exon 1 of 3	NP_001010867.1	Q5T440

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IBA57	ENST00000366711.4	TSL:2 MANE Select	c.150C>A	p.Cys50*	stop_gained	Exon 1 of 3	ENSP00000355672.3	Q5T440
	IBA57	ENST00000949083.1		c.150C>A	p.Cys50*	stop_gained	Exon 1 of 3	ENSP00000619142.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1363684 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 672844

African (AFR) AF: 0.00 AC: 0 AN: 28520

American (AMR) AF: 0.00 AC: 0 AN: 33992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24316

East Asian (EAS) AF: 0.00 AC: 0 AN: 33230

South Asian (SAS) AF: 0.00 AC: 0 AN: 76566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4552

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071820

Other (OTH) AF: 0.00 AC: 0 AN: 56940

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Multiple mitochondrial dysfunctions syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Uncertain	0.27
Eigen_PC	Benign	-0.0011
FATHMM_MKL	Benign	0.50	D
PhyloP100		0.89
Vest4		0.093
GERP RS		2.0
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=6/194	disease causing (ClinVar)

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: rs765132163; hg19: chr1-228353667;