12-108562641-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000392807.8(ISCU):c.-153T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.876 in 1,468,804 control chromosomes in the GnomAD database, including 564,017 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 56937 hom., cov: 36)

Exomes 𝑓: 0.88 ( 507080 hom. )

Consequence

ISCU
ENST00000392807.8 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.46

Publications

21 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.0388344E-7).

BP6

Variant 12-108562641-T-G is Benign according to our data. Variant chr12-108562641-T-G is described in ClinVar as [Benign]. Clinvar id is 768575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISCU	NM_213595.4 link	c.19T>G	p.Phe7Val	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.19T>G	p.Phe7Val	missense_variant	Exon 1 of 5	1	NM_213595.4	ENSP00000310623.9		Q9H1K1-1

Frequencies

GnomAD3 genomes

AF:

0.865

AC:

131379

AN:

151914

Hom.:

56880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.832

Gnomad AMI

AF:

0.873

Gnomad AMR

AF:

0.867

Gnomad ASJ

AF:

0.895

Gnomad EAS

AF:

0.938

Gnomad SAS

AF:

0.932

Gnomad FIN

AF:

0.843

Gnomad MID

AF:

0.885

Gnomad NFE

AF:

0.876

Gnomad OTH

AF:

0.854

GnomAD2 exomes

AF:

0.864

AC:

84714

AN:

98058

AF XY:

0.866

show subpopulations

Gnomad AFR exome

AF:

0.780

Gnomad AMR exome

AF:

0.848

Gnomad ASJ exome

AF:

0.878

Gnomad EAS exome

AF:

0.916

Gnomad FIN exome

AF:

0.825

Gnomad NFE exome

AF:

0.853

Gnomad OTH exome

AF:

0.852

GnomAD4 exome

AF:

0.877

AC:

1154596

AN:

1316774

Hom.:

507080

Cov.:

AF XY:

0.878

AC XY:

569976

AN XY:

649020

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.836

AC:

22532

AN:

26940

American (AMR)

AF:

0.859

AC:

24086

AN:

28032

Ashkenazi Jewish (ASJ)

AF:

0.888

AC:

20013

AN:

22530

East Asian (EAS)

AF:

0.941

AC:

28589

AN:

30380

South Asian (SAS)

AF:

0.925

AC:

65326

AN:

70654

European-Finnish (FIN)

AF:

0.847

AC:

27406

AN:

32366

Middle Eastern (MID)

AF:

0.886

AC:

3995

AN:

4510

European-Non Finnish (NFE)

AF:

0.874

AC:

914505

AN:

1046678

Other (OTH)

AF:

0.880

AC:

48144

AN:

54684

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.393

Heterozygous variant carriers

5646

11292

16937

22583

28229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.865

AC:

131495

AN:

152030

Hom.:

56937

Cov.:

AF XY:

0.865

AC XY:

64277

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.832

AC:

34521

AN:

41470

American (AMR)

AF:

0.867

AC:

13276

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.895

AC:

3106

AN:

3472

East Asian (EAS)

AF:

0.938

AC:

4837

AN:

5154

South Asian (SAS)

AF:

0.931

AC:

4499

AN:

4830

European-Finnish (FIN)

AF:

0.843

AC:

8914

AN:

10574

Middle Eastern (MID)

AF:

0.883

AC:

256

AN:

290

European-Non Finnish (NFE)

AF:

0.876

AC:

59492

AN:

67922

Other (OTH)

AF:

0.856

AC:

1807

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

961

1922

2884

3845

4806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.870

Hom.:

9535

Bravo

AF:

0.864

ExAC

AF:

0.844

AC:

83727

Asia WGS

AF:

0.944

AC:

3256

AN:

3450

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary myopathy with lactic acidosis due to ISCU deficiency

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.053

.;T;.;T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.00089

LIST_S2

Benign

0.21

.;T;T;T;T

MetaRNN

Benign

8.0e-7

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

.;.;.;N;.

PhyloP100

2.5

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.18

N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.52

T;T;T;T;T

Sift4G

Benign

0.52

T;T;T;T;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.20

MPC

0.46

ClinPred

0.042

GERP RS

5.0

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.055

gMVP

0.62

Mutation Taster

=298/2

polymorphism (auto)

(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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12-108562641-T-G

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