rs745953998

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_213595.4(ISCU):c.29G>A(p.Arg10Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,462,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R10S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 37)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ISCU
NM_213595.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.073880225).

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>A	p.Arg10Lys	missense	Exon 1 of 5	NP_998760.1	Q9H1K1-1
ISCU	NM_001301141.1		c.29G>A	p.Arg10Lys	missense	Exon 1 of 6	NP_001288070.1	B3KQ30
ISCU	NM_001301140.1		c.29G>A	p.Arg10Lys	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>A	p.Arg10Lys	missense	Exon 1 of 5	ENSP00000310623.9	Q9H1K1-1
ISCU	ENST00000392807.8	TSL:1	c.-143G>A		5_prime_UTR	Exon 1 of 6	ENSP00000376554.4	Q9H1K1-2
ISCU	ENST00000539580.5	TSL:1	n.29G>A		non_coding_transcript_exon	Exon 1 of 7	ENSP00000437854.1	F5H672

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000386

AC:

AN:

77810

AF XY:

0.0000445

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000653

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000486

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000114

AC:

AN:

1310490

Hom.:

Cov.:

AF XY:

0.00000931

AC XY:

AN XY:

644628

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26660

American (AMR)

AF:

0.0000373

AC:

AN:

26804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21898

East Asian (EAS)

AF:

0.000440

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:

9.56e-7

AC:

AN:

1045688

Other (OTH)

AF:

0.00

AC:

AN:

54470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000822

AC:

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

0.31

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.066

Eigen

Benign

0.074

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

PhyloP100

2.4

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.24

REVEL

Benign

0.16

Sift

Benign

0.27

Sift4G

Benign

0.52

Polyphen

0.84

Vest4

0.50

MutPred

0.29

Loss of methylation at R10 (P = 0.0157)

MVP

0.68

MPC

0.35

ClinPred

0.25

GERP RS

5.3

PromoterAI

-0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.66

Mutation Taster

=81/19

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over