12-108562632-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_213595.4(ISCU):c.10G>C(p.Ala4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00528 in 1,473,674 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0036 ( 0 hom., cov: 35)

Exomes 𝑓: 0.0055 ( 42 hom. )

Consequence

ISCU
NM_213595.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 1.60

Publications

3 publications found

Variant links:

Genes affected

ISCU (HGNC:29882): (iron-sulfur cluster assembly enzyme) This gene encodes a component of the iron-sulfur (Fe-S) cluster scaffold. Fe-S clusters are cofactors that play a role in the function of a diverse set of enzymes, including those that regulate metabolism, iron homeostasis, and oxidative stress response. Alternative splicing results in transcript variants encoding different protein isoforms that localize either to the cytosol or to the mitochondrion. Mutations in this gene have been found in patients with hereditary myopathy with lactic acidosis. A disease-associated mutation in an intron may activate a cryptic splice site, resulting in the production of a splice variant encoding a putatively non-functional protein. A pseudogene of this gene is present on chromosome 1. [provided by RefSeq, Feb 2016]

ISCU Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary myopathy with lactic acidosis due to ISCU deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ISCU links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009756267).

BP6

Variant 12-108562632-G-C is Benign according to our data. Variant chr12-108562632-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214555.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High Homozygotes in GnomAdExome4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISCU	NM_213595.4 link	c.10G>C	p.Ala4Pro	missense_variant	Exon 1 of 5	ENST00000311893.14	NP_998760.1	Q9H1K1-1B3KQ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISCU	ENST00000311893.14 link	c.10G>C	p.Ala4Pro	missense_variant	Exon 1 of 5	1	NM_213595.4	ENSP00000310623.9		Q9H1K1-1

Frequencies

GnomAD3 genomes

AF:

0.00365

AC:

556

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00630

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00606

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00197

AC:

189

AN:

95794

AF XY:

0.00200

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.000904

Gnomad ASJ exome

AF:

0.00173

Gnomad EAS exome

AF:

0.000200

Gnomad FIN exome

AF:

0.00253

Gnomad NFE exome

AF:

0.00256

Gnomad OTH exome

AF:

0.000391

GnomAD4 exome

AF:

0.00547

AC:

7227

AN:

1321316

Hom.:

Cov.:

AF XY:

0.00533

AC XY:

3468

AN XY:

650944

show subpopulations

African (AFR)

AF:

0.000554

AC:

AN:

27082

American (AMR)

AF:

0.00103

AC:

AN:

28062

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

22630

East Asian (EAS)

AF:

0.0000329

AC:

AN:

30374

South Asian (SAS)

AF:

0.00436

AC:

307

AN:

70480

European-Finnish (FIN)

AF:

0.00461

AC:

149

AN:

32356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4484

European-Non Finnish (NFE)

AF:

0.00611

AC:

6426

AN:

1050988

Other (OTH)

AF:

0.00452

AC:

248

AN:

54860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

279

558

836

1115

1394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00365

AC:

556

AN:

152358

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

286

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000793

AC:

AN:

41596

American (AMR)

AF:

0.000719

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00393

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00630

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00606

AC:

412

AN:

68026

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00304

Hom.:

Bravo

AF:

0.00317

ExAC

AF:

0.00157

AC:

161

Asia WGS

AF:

0.00145

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Dec 14, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 28, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ISCU: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary myopathy with lactic acidosis due to ISCU deficiency

Uncertain:1Benign:1

Sep 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 21, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ISCU-related disorder

Benign:1

Jan 20, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.081

.;T;.;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.087

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.63

.;T;T;T;T

MetaRNN

Benign

0.0098

T;T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.0

.;.;.;N;.

PhyloP100

1.6

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.75

N;N;N;N;N

REVEL

Benign

0.27

Sift

Uncertain

0.0060

D;D;D;D;D

Sift4G

Uncertain

0.040

D;D;D;T;D

Polyphen

0.27

B;P;B;D;P

Vest4

0.53

MVP

0.75

MPC

0.45

ClinPred

0.069

GERP RS

4.4

PromoterAI

-0.086

Neutral

(source)

Varity_R

0.33

gMVP

0.76

Mutation Taster

=291/9

polymorphism

(source)

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

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12-108562632-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over