12-108562632-G-C

Position:

chr12-108562632-G-C

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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 links:

ISCU (HGNC:):

ISCU links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 submissions are: {Likely_benign=5, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ISCU	NM_213595.4 linkuse as main transcript	c.10G>C	p.Ala4Pro	missense_variant	1/5	ENST00000311893.14	NP_998760.1	Q9H1K1-1B3KQ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ISCU	ENST00000311893.14 linkuse as main transcript	c.10G>C	p.Ala4Pro	missense_variant	1/5	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

GnomAD3 exomes

AF:

0.00197

AC:

189

AN:

95794

Hom.:

AF XY:

0.00200

AC XY:

111

AN XY:

55494

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 SAS exome

AF:

0.00239

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

Gnomad4 AFR exome

AF:

0.000554

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00230

Gnomad4 EAS exome

AF:

0.0000329

Gnomad4 SAS exome

AF:

0.00436

Gnomad4 FIN exome

AF:

0.00461

Gnomad4 NFE exome

AF:

0.00611

Gnomad4 OTH exome

AF:

0.00452

GnomAD4 genome

AF:

0.00365

AC:

556

AN:

152358

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

286

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000793

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.00630

Gnomad4 NFE

AF:

0.00606

Gnomad4 OTH

AF:

0.00425

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ISCU: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 28, 2023	- -

Hereditary myopathy with lactic acidosis due to ISCU deficiency

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 21, 2021	- -

ISCU-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2020

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

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;.

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

Varity_R

0.33

gMVP

0.76

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