12-108568592-G-A

Variant names:

• chr12-108568592-G-A
• rs880844
• NM_213595.4:c.419-239G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.198
• Publications: 6 publications found

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

ACMG classification

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
ISCU	NM_213595.4	c.419-239G>A		intron_variant	Intron 4 of 4	ENST00000311893.14	NP_998760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISCU	ENST00000311893.14	c.419-239G>A		intron_variant	Intron 4 of 4	1	NM_213595.4	ENSP00000310623.9

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30283 AN: 152064 Hom.: 3870 Cov.: 32

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

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

GnomAD4 genome AF: 0.199 AC: 30283 AN: 152182 Hom.: 3870 Cov.: 32 AF XY: 0.205 AC XY: 15273 AN XY: 74386

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

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

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

Other links and lift over

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