Genetic Variant ISCU:p.Arg8Gly (chr12-108562644-C-G) – 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.22C>G(p.Arg8Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 36)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ISCU
NM_213595.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.03

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:

Genome browser will be placed here

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.22C>G	p.Arg8Gly	missense	Exon 1 of 5	NP_998760.1	Q9H1K1-1
ISCU	NM_001301141.1		c.22C>G	p.Arg8Gly	missense	Exon 1 of 6	NP_001288070.1	B3KQ30
ISCU	NM_001301140.1		c.22C>G	p.Arg8Gly	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.22C>G	p.Arg8Gly	missense	Exon 1 of 5	ENSP00000310623.9	Q9H1K1-1
ISCU	ENST00000392807.8	TSL:1	c.-150C>G		5_prime_UTR	Exon 1 of 6	ENSP00000376554.4	Q9H1K1-2
ISCU	ENST00000539580.5	TSL:1	n.22C>G		non_coding_transcript_exon	Exon 1 of 7	ENSP00000437854.1	F5H672

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1329816

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

656052

African (AFR)

AF:

0.00

AC:

AN:

27216

American (AMR)

AF:

0.00

AC:

AN:

28990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22748

East Asian (EAS)

AF:

0.00

AC:

AN:

30482

South Asian (SAS)

AF:

0.00

AC:

AN:

71514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4662

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1056398

Other (OTH)

AF:

0.00

AC:

AN:

55156

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.094

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.82

M_CAP

Benign

0.079

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

1.0

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.1

REVEL

Benign

0.21

Sift

Uncertain

0.011

Sift4G

Benign

0.32

Polyphen

0.65

Vest4

0.36

MutPred

0.33

Loss of methylation at R8 (P = 0.0037)

MVP

0.71

MPC

0.45

ClinPred

0.53

GERP RS

5.0

PromoterAI

0.045

Neutral

(source)

Varity_R

0.24

gMVP

0.67

Mutation Taster

=283/17

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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