Genetic Variant ISCU:p.Arg10Thr (chr12-108562651-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_213595.4(ISCU):c.29G>C(p.Arg10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R10S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 37)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ISCU
NM_213595.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.42

Publications

1 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213595.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ISCU	NM_213595.4	MANE Select	c.29G>C	p.Arg10Thr	missense	Exon 1 of 5	NP_998760.1	Q9H1K1-1
ISCU	NM_001301141.1		c.29G>C	p.Arg10Thr	missense	Exon 1 of 6	NP_001288070.1	B3KQ30
ISCU	NM_001301140.1		c.29G>C	p.Arg10Thr	missense	Exon 1 of 6	NP_001288069.1	B3KQ30

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ISCU	ENST00000311893.14	TSL:1 MANE Select	c.29G>C	p.Arg10Thr	missense	Exon 1 of 5	ENSP00000310623.9	Q9H1K1-1
ISCU	ENST00000392807.8	TSL:1	c.-143G>C		5_prime_UTR	Exon 1 of 6	ENSP00000376554.4	Q9H1K1-2
ISCU	ENST00000539580.5	TSL:1	n.29G>C		non_coding_transcript_exon	Exon 1 of 7	ENSP00000437854.1	F5H672

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

77810

AF XY:

0.00

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1310490

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

644628

African (AFR)

AF:

0.00

AC:

AN:

26660

American (AMR)

AF:

0.00

AC:

AN:

26804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21898

East Asian (EAS)

AF:

0.00

AC:

AN:

29532

South Asian (SAS)

AF:

0.00

AC:

AN:

69102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4744

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1045688

Other (OTH)

AF:

0.00

AC:

AN:

54470

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.0

PhyloP100

2.4

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.71

REVEL

Benign

0.17

Sift

Uncertain

0.016

Sift4G

Benign

0.30

Polyphen

0.97

Vest4

0.59

MutPred

0.42

Loss of methylation at R10 (P = 0.007)

MVP

0.76

MPC

0.52

ClinPred

0.44

GERP RS

5.3

PromoterAI

0.063

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.71

Mutation Taster

=80/20

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over