rs776679653

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_030940.4(ISCA1):c.259G>A(p.Glu87Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000995 in 1,607,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ISCA1
NM_030940.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1O:1

Conservation

PhyloP100: 7.57

Publications

13 publications found

Variant links:

Genes affected

ISCA1 (HGNC:28660): (iron-sulfur cluster assembly 1) ISCA1 is a mitochondrial protein involved in the biogenesis and assembly of iron-sulfur clusters, which play a role in electron-transfer reactions (Cozar-Castellano et al., 2004 [PubMed 15262227]).[supplied by OMIM, Mar 2008]

ISCA1 Gene-Disease associations (from GenCC):

multiple mitochondrial dysfunctions syndrome 5
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ISCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.78379 (below the threshold of 3.09). Trascript score misZ: 0.56687 (below the threshold of 3.09). GenCC associations: The gene is linked to multiple mitochondrial dysfunctions syndrome 5.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

PP5

Variant 9-86266174-C-T is Pathogenic according to our data. Variant chr9-86266174-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 375415.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030940.4. 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
	ISCA1	NM_030940.4	MANE Select	c.259G>A	p.Glu87Lys	missense	Exon 4 of 4	NP_112202.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ISCA1	ENST00000375991.9	TSL:1 MANE Select	c.259G>A	p.Glu87Lys	missense	Exon 4 of 4	ENSP00000365159.4	Q9BUE6-1
ISCA1	ENST00000637705.1	TSL:5	c.196G>A	p.Glu66Lys	missense	Exon 4 of 4	ENSP00000489740.1	A0A1B0GTK6
ISCA1	ENST00000311534.6	TSL:2	c.-36G>A		5_prime_UTR	Exon 4 of 4	ENSP00000339003.4	Q5TBE2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000416

AC:

AN:

240416

AF XY:

0.00000770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000103

AC:

AN:

1455516

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

723626

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33068

American (AMR)

AF:

0.00

AC:

AN:

43300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25832

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000236

AC:

AN:

84690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1109798

Other (OTH)

AF:

0.0000166

AC:

AN:

60098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Multiple mitochondrial dysfunctions syndrome 5 (4)

Fatal multiple mitochondrial dysfunctions syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0089

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.5

PhyloP100

7.6

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.34

Sift

Benign

0.033

Sift4G

Benign

0.080

Polyphen

0.62

Vest4

0.61

MutPred

0.76

Gain of MoRF binding (P = 0.0235)

MVP

0.30

MPC

0.92

ClinPred

0.92

GERP RS

5.7

Varity_R

0.56

gMVP

0.87

Mutation Taster

=160/140

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over