dbSNP rs767000507: ISCU:c.418+382G>C (chr12-108567650-G-C) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3PM2PP5_Very_StrongBP4

The NM_001301140.1(ISCU):c.419-8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000606 in 1,535,182 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003441167: Experimental studies have shown that this variant affects ISCU function (PMID:18304497, 19846308, 30209894).".

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000067 ( 1 hom. )

Consequence

ISCU
NM_001301140.1 splice_region, intron

Scores

Splicing: ADA: 0.00009216

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 1.22

Publications

3 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: Pathogenic. The variant received 13 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV003441167: Experimental studies have shown that this variant affects ISCU function (PMID: 18304497, 19846308, 30209894).

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-108567650-G-C is Pathogenic according to our data. Variant chr12-108567650-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 223141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301140.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ISCU	NM_213595.4	MANE Select	c.418+382G>C	intron	N/A	NP_998760.1	Q9H1K1-1
ISCU	NM_001301141.1		c.419-270G>C	intron	N/A	NP_001288070.1	B3KQ30
ISCU	NM_001301140.1		c.419-8G>C	splice_region intron	N/A	NP_001288069.1	B3KQ30

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ISCU	ENST00000311893.14	TSL:1 MANE Select	c.418+382G>C	intron	N/A	ENSP00000310623.9	Q9H1K1-1
ISCU	ENST00000392807.8	TSL:1	c.343+382G>C	intron	N/A	ENSP00000376554.4	Q9H1K1-2
ISCU	ENST00000539580.5	TSL:1	n.*374-8G>C	splice_region intron	N/A	ENSP00000437854.1	F5H672

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000224

AC:

AN:

134050

AF XY:

0.0000137

show subpopulations

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:

0.0000571

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000665

AC:

AN:

1382960

Hom.:

Cov.:

AF XY:

0.0000557

AC XY:

AN XY:

682526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31566

American (AMR)

AF:

0.00

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.00

AC:

AN:

35726

South Asian (SAS)

AF:

0.00

AC:

AN:

79224

European-Finnish (FIN)

AF:

0.000177

AC:

AN:

33830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.0000751

AC:

AN:

1078174

Other (OTH)

AF:

0.0000864

AC:

AN:

57872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary myopathy with lactic acidosis due to ISCU deficiency (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.47

PhyloP100

1.2

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000092

dbscSNV1_RF

Benign

0.0040

Splicevardb

3.0

SpliceAI score (max)

0.17

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