chr12-108568592-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_213595.4(ISCU):​c.419-239G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,391,868 control chromosomes in the GnomAD database, including 47,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3870 hom., cov: 32)
Exomes 𝑓: 0.26 ( 43395 hom. )

Consequence

ISCU
NM_213595.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.198

Publications

6 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 12-108568592-G-A is Benign according to our data. Variant chr12-108568592-G-A is described in ClinVar as [Benign]. Clinvar id is 681977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ISCUNM_213595.4 linkc.419-239G>A intron_variant Intron 4 of 4 ENST00000311893.14 NP_998760.1 Q9H1K1-1B3KQ30

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ISCUENST00000311893.14 linkc.419-239G>A intron_variant Intron 4 of 4 1 NM_213595.4 ENSP00000310623.9 Q9H1K1-1

Frequencies

GnomAD3 genomes
AF:
0.199
AC:
30283
AN:
152064
Hom.:
3870
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0473
Gnomad AMI
AF:
0.131
Gnomad AMR
AF:
0.180
Gnomad ASJ
AF:
0.191
Gnomad EAS
AF:
0.492
Gnomad SAS
AF:
0.360
Gnomad FIN
AF:
0.296
Gnomad MID
AF:
0.165
Gnomad NFE
AF:
0.248
Gnomad OTH
AF:
0.205
GnomAD4 exome
AF:
0.258
AC:
319501
AN:
1239686
Hom.:
43395
Cov.:
28
AF XY:
0.261
AC XY:
156373
AN XY:
600028
show subpopulations
African (AFR)
AF:
0.0393
AC:
1072
AN:
27262
American (AMR)
AF:
0.176
AC:
3243
AN:
18378
Ashkenazi Jewish (ASJ)
AF:
0.198
AC:
3494
AN:
17650
East Asian (EAS)
AF:
0.490
AC:
15290
AN:
31222
South Asian (SAS)
AF:
0.336
AC:
20404
AN:
60660
European-Finnish (FIN)
AF:
0.296
AC:
7345
AN:
24798
Middle Eastern (MID)
AF:
0.221
AC:
799
AN:
3622
European-Non Finnish (NFE)
AF:
0.253
AC:
254797
AN:
1005378
Other (OTH)
AF:
0.257
AC:
13057
AN:
50716
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
11963
23925
35888
47850
59813
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
9376
18752
28128
37504
46880
<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:
0.199
AC:
30283
AN:
152182
Hom.:
3870
Cov.:
32
AF XY:
0.205
AC XY:
15273
AN XY:
74386
show subpopulations
African (AFR)
AF:
0.0472
AC:
1962
AN:
41548
American (AMR)
AF:
0.180
AC:
2747
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.191
AC:
662
AN:
3470
East Asian (EAS)
AF:
0.493
AC:
2555
AN:
5180
South Asian (SAS)
AF:
0.359
AC:
1728
AN:
4810
European-Finnish (FIN)
AF:
0.296
AC:
3132
AN:
10574
Middle Eastern (MID)
AF:
0.170
AC:
50
AN:
294
European-Non Finnish (NFE)
AF:
0.248
AC:
16895
AN:
68006
Other (OTH)
AF:
0.205
AC:
433
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
1186
2373
3559
4746
5932
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
328
656
984
1312
1640
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.239
Hom.:
2323
Bravo
AF:
0.184
Asia WGS
AF:
0.400
AC:
1389
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jun 14, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
1.9
DANN
Benign
0.61
PhyloP100
-0.20
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs880844; hg19: chr12-108962368; COSMIC: COSV108143164; COSMIC: COSV108143164; API