12-108562653-C-A

Variant names:

• chr12-108562653-C-A
• rs761091987
• NM_213595.4:c.31C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_213595.4(ISCU):​c.31C>A​(p.Arg11Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000613 in 1,305,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 0.0000061 (0 hom.)
• Consequence: ISCU NM_213595.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0130
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP7: Synonymous conserved (PhyloP=-0.013 with no splicing effect.

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.31C>A	p.Arg11Arg	synonymous	Exon 1 of 5	NP_998760.1	Q9H1K1-1
	ISCU	NM_001301141.1		c.31C>A	p.Arg11Arg	synonymous	Exon 1 of 6	NP_001288070.1	B3KQ30
	ISCU	NM_001301140.1		c.31C>A	p.Arg11Arg	synonymous	Exon 1 of 6	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.31C>A	p.Arg11Arg	synonymous	Exon 1 of 5	ENSP00000310623.9	Q9H1K1-1
	ISCU	ENST00000392807.8	TSL:1	c.-141C>A		5_prime_UTR	Exon 1 of 6	ENSP00000376554.4	Q9H1K1-2
	ISCU	ENST00000539580.5	TSL:1	n.31C>A		non_coding_transcript_exon	Exon 1 of 7	ENSP00000437854.1	F5H672

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD2 exomes AF: 0.0000274 AC: 2 AN: 73030 AF XY: 0.0000478

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000613 AC: 8 AN: 1305974 Hom.: 0 Cov.: 34 AF XY: 0.0000109 AC XY: 7 AN XY: 641848

African (AFR) AF: 0.00 AC: 0 AN: 26592

American (AMR) AF: 0.00 AC: 0 AN: 26530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21602

East Asian (EAS) AF: 0.00 AC: 0 AN: 29500

South Asian (SAS) AF: 0.000117 AC: 8 AN: 68134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1043304

Other (OTH) AF: 0.00 AC: 0 AN: 54286

GnomAD4 genome Cov.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.8
DANN	Benign	0.83
PhyloP100		-0.013
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs761091987; hg19: chr12-108956429;