rs759005478

Variant names:

• chr1-228166121-T-C
• rs759005478
• NM_001010867.4:c.305T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-228166121-T-C
• chr1-228166121-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001010867.4(IBA57):​c.305T>C​(p.Val102Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,384,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V102G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: IBA57 NM_001010867.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001010867.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31667024).

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.305T>C	p.Val102Ala	missense	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.305T>C	p.Val102Ala	missense	Exon 1 of 3	ENSP00000355672.3	Q5T440
	IBA57	ENST00000949083.1		c.305T>C	p.Val102Ala	missense	Exon 1 of 3	ENSP00000619142.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000227 AC: 3 AN: 132128 AF XY: 0.0000274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1384606 Hom.: 0 Cov.: 33 AF XY: 0.00000292 AC XY: 2 AN XY: 683834

African (AFR) AF: 0.00 AC: 0 AN: 29738

American (AMR) AF: 0.0000884 AC: 3 AN: 33922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24512

East Asian (EAS) AF: 0.00 AC: 0 AN: 34874

South Asian (SAS) AF: 0.00 AC: 0 AN: 77446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076196

Other (OTH) AF: 0.00 AC: 0 AN: 57504

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Multiple mitochondrial dysfunctions syndrome 3;C5568837:Hereditary spastic paraplegia 74 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.058
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.87	L
PhyloP100		2.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.18
Sift	Benign	0.10	T
Sift4G	Benign	0.39	T
Polyphen		0.11	B
Vest4		0.31
MutPred		0.64		Gain of sheet (P = 0.0477)
MVP		0.67
MPC		0.38
ClinPred		0.42	T
GERP RS		4.3
PromoterAI		0.047	Neutral
Varity_R		0.57
gMVP		0.55
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs759005478; hg19: chr1-228353822;