Genetic Variant NM_213595.4:c.14G>T (chr12-108562636-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_213595.4(ISCU):c.14G>T(p.Gly5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000753 in 1,327,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G5A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

ISCU
NM_213595.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.43

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32753158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISCU	NM_213595.4 link	c.14G>T	p.Gly5Val	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.14G>T	p.Gly5Val	missense_variant	Exon 1 of 5	1	NM_213595.4	ENSP00000310623.9		Q9H1K1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.53e-7

AC:

AN:

1327288

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

654264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27212

American (AMR)

AF:

0.00

AC:

AN:

28670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22768

East Asian (EAS)

AF:

0.00

AC:

AN:

30548

South Asian (SAS)

AF:

0.00

AC:

AN:

71172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4590

European-Non Finnish (NFE)

AF:

9.48e-7

AC:

AN:

1054612

Other (OTH)

AF:

0.00

AC:

AN:

55156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.063

.;T;.;T;.

Eigen

Benign

-0.038

Eigen_PC

Benign

0.060

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.84

.;T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.33

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

.;.;.;N;.

PhyloP100

2.4

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.69

N;N;N;N;N

REVEL

Benign

0.22

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Benign

0.081

T;T;T;T;T

Polyphen

0.74

P;P;P;B;P

Vest4

0.50

MutPred

0.36

Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);

MVP

0.75

MPC

0.44

ClinPred

0.71

GERP RS

4.0

PromoterAI

0.067

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.63

Mutation Taster

=267/33

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over