chr1-228174936-T-G

Variant names:

• chr1-228174936-T-G
• rs1553264669
• NM_001010867.4:c.586T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001010867.4(IBA57):​c.586T>G​(p.Trp196Gly) variant causes a missense 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).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IBA57 NM_001010867.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.53
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant 1-228174936-T-G is Pathogenic according to our data. Variant chr1-228174936-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 545646.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IBA57	NM_001010867.4	MANE Select	c.586T>G	p.Trp196Gly	missense	Exon 2 of 3	NP_001010867.1
	IBA57	NM_001310327.2		c.7T>G	p.Trp3Gly	missense	Exon 2 of 3	NP_001297256.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IBA57	ENST00000366711.4	TSL:2 MANE Select	c.586T>G	p.Trp196Gly	missense	Exon 2 of 3	ENSP00000355672.3
	IBA57	ENST00000484749.5	TSL:5	n.2586T>G		non_coding_transcript_exon	Exon 2 of 3
	IBA57	ENST00000546123.2	TSL:2	n.306T>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 3 Pathogenic:1

Jun 25, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.097	T
Eigen	Benign	0.0015
Eigen_PC	Benign	0.082
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.43
Sift	Benign	0.062	T
Sift4G	Benign	0.31	T
Polyphen		0.17	B
Vest4		0.94
MutPred		0.77		Gain of disorder (P = 0.0011)
MVP		0.79
MPC		0.78
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.84
gMVP		0.91
Mutation Taster		=8/92	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: rs1553264669; hg19: chr1-228362637;