rs67681514

Variant names:

• chr12-108562641-TT-GG
• rs67681514
• NM_213595.4:c.19_20delTTinsGG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_213595.4(ISCU):​c.19_20delTTinsGG​(p.Phe7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.859 in 110,974 alleles, including 48,105 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F7V) has been classified as Benign.

• Frequency: GnomAD MNV: 𝑓 0.86 Genomes: not found (cov: 35)
• Consequence: ISCU NM_213595.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.46
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 12-108562641-TT-GG is Benign according to our data. Variant chr12-108562641-TT-GG is described in ClinVar as Benign. ClinVar VariationId is 559220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdMnv highest population allele frequency = 0.859 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISCU	NM_213595.4	MANE Select	c.19_20delTTinsGG	p.Phe7Gly	missense	N/A	NP_998760.1	Q9H1K1-1
	ISCU	NM_001301141.1		c.19_20delTTinsGG	p.Phe7Gly	missense	N/A	NP_001288070.1	B3KQ30
	ISCU	NM_001301140.1		c.19_20delTTinsGG	p.Phe7Gly	missense	N/A	NP_001288069.1	B3KQ30

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISCU	ENST00000311893.14	TSL:1 MANE Select	c.19_20delTTinsGG	p.Phe7Gly	missense	N/A	ENSP00000310623.9	Q9H1K1-1
	ISCU	ENST00000392807.8	TSL:1	c.-153_-152delTTinsGG		5_prime_UTR	Exon 1 of 6	ENSP00000376554.4	Q9H1K1-2
	ISCU	ENST00000539580.5	TSL:1	n.19_20delTTinsGG		non_coding_transcript_exon	Exon 1 of 7	ENSP00000437854.1	F5H672

Frequencies

GnomAD3 genomes Cov.: 35

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 35

GnomAD MNV AF: 0.859 AC: 110974 Hom.: 48105

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary myopathy with lactic acidosis due to ISCU deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs67681514; hg19: chr12-108956417; COSMIC: COSV108092780; COSMIC: COSV108092780;