NM_213595.4:c.79dupG

Variant names:

• chr12-108562698-C-CG
• rs57304020
• NM_213595.4:c.79dupG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_213595.4(ISCU):​c.79dupG​(p.Glu27GlyfsTer15) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E27E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: ISCU NM_213595.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.82
• Publications: 1 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: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISCU	NM_213595.4	MANE Select	c.79dupG	p.Glu27GlyfsTer15	frameshift	Exon 1 of 5	NP_998760.1
	ISCU	NM_001301141.1		c.79dupG	p.Glu27GlyfsTer15	frameshift	Exon 1 of 6	NP_001288070.1
	ISCU	NM_001301140.1		c.79dupG	p.Glu27GlyfsTer15	frameshift	Exon 1 of 6	NP_001288069.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISCU	ENST00000311893.14	TSL:1 MANE Select	c.79dupG	p.Glu27GlyfsTer15	frameshift	Exon 1 of 5	ENSP00000310623.9
	ISCU	ENST00000539580.5	TSL:1	n.79dupG		non_coding_transcript_exon	Exon 1 of 7	ENSP00000437854.1
	ISCU	ENST00000392807.8	TSL:1	c.-93dupG		5_prime_UTR	Exon 1 of 6	ENSP00000376554.4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8

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: rs57304020; hg19: chr12-108956474;