rs778755775

Positions:

chr14-74494829-AT-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_194279.4(ISCA2):c.297del(p.Phe99LeufsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

ISCA2
NM_194279.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1O:1

Conservation

PhyloP100: 7.83

Variant links:

Genes affected

ISCA2 (HGNC:19857): (iron-sulfur cluster assembly 2) The protein encoded by this gene is an A-type iron-sulfur cluster (ISC) protein found in mitochondria. The encoded protein appears to be involved in the maturation of mitochondrial iron-sulfur proteins. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ISCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.366 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-74494829-AT-A is Pathogenic according to our data. Variant chr14-74494829-AT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 545531.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, not_provided=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ISCA2	NM_194279.4 linkuse as main transcript	c.297del	p.Phe99LeufsTer18	frameshift_variant	4/4	ENST00000556816.6	NP_919255.2
ISCA2	NM_001272007.2 linkuse as main transcript	c.181del	p.Ter61GlufsTer56	frameshift_variant	3/3		NP_001258936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ISCA2	ENST00000556816.6 linkuse as main transcript	c.297del	p.Phe99LeufsTer18	frameshift_variant	4/4	1	NM_194279.4	ENSP00000452007	P1	Q86U28-1
ISCA2	ENST00000554924.1 linkuse as main transcript	c.181del	p.Ter61GlufsTer56	frameshift_variant	3/3	2		ENSP00000450523		Q86U28-2
ISCA2	ENST00000298818.12 linkuse as main transcript	c.305-7del		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000298818
ISCA2	ENST00000555139.1 linkuse as main transcript	n.735del		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250972

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135616

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000691

AC:

101

AN:

1461610

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727118

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000890

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2018	The c.297delT variant has been published in a two month old presenting with severe hypotonia and nystagmus who had decreased activities of complex II and IV in muscle tissue and who harbored a second variant in the ISCA2 gene on the opposite allele (in trans) (Toldo et al., 2018). The c.297delT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.297delT variant causes a frameshift starting with codon Phenylalanine 99, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Phe99LeufsX18 (F99LfsX18). This variant is predicted to cause loss of normal protein function through protein truncation. In summary, we interpret c.297delT as a likely pathogenic variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 30, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 545531). This premature translational stop signal has been observed in individual(s) with clinical features consistent with multiple mitochondrial dysfunctions syndrome (PMID: 29359243). This variant is present in population databases (rs778755775, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Phe99Leufs*18) in the ISCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 56 amino acid(s) of the ISCA2 protein. -

Multiple mitochondrial dysfunctions syndrome 4

Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over