12-108569028-C-T

Variant names:

• chr12-108569028-C-T
• rs10187
• ENST00000539580.5:n.*671C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000539580.5(ISCU):​n.*671C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0428 in 834,998 control chromosomes in the GnomAD database, including 989 homozygotes. 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: 𝑓 0.033 (114 hom., cov: 33)
  • Exomes 𝑓: 0.045 (875 hom.)
• Consequence: ISCU ENST00000539580.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.690
• Publications: 12 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.064 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISCU	NM_213595.4	c.*112C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000311893.14	NP_998760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISCU	ENST00000311893.14	c.*112C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_213595.4	ENSP00000310623.9

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5081 AN: 152198 Hom.: 114 Cov.: 33

Gnomad AFR AF: 0.00760

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.0354

Gnomad ASJ AF: 0.0730

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0697

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0473

Gnomad OTH AF: 0.0353

GnomAD4 exome AF: 0.0450 AC: 30689 AN: 682682 Hom.: 875 Cov.: 9 AF XY: 0.0472 AC XY: 16988 AN XY: 359708

African (AFR) AF: 0.00944 AC: 166 AN: 17584

American (AMR) AF: 0.0376 AC: 1266 AN: 33698

Ashkenazi Jewish (ASJ) AF: 0.0692 AC: 1417 AN: 20484

East Asian (EAS) AF: 0.00224 AC: 73 AN: 32606

South Asian (SAS) AF: 0.0777 AC: 5006 AN: 64450

European-Finnish (FIN) AF: 0.0250 AC: 1086 AN: 43402

Middle Eastern (MID) AF: 0.0699 AC: 188 AN: 2690

European-Non Finnish (NFE) AF: 0.0462 AC: 20026 AN: 433330

Other (OTH) AF: 0.0424 AC: 1461 AN: 34438

GnomAD4 genome AF: 0.0334 AC: 5086 AN: 152316 Hom.: 114 Cov.: 33 AF XY: 0.0329 AC XY: 2453 AN XY: 74490

African (AFR) AF: 0.00767 AC: 319 AN: 41570

American (AMR) AF: 0.0353 AC: 540 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0730 AC: 253 AN: 3468

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5186

South Asian (SAS) AF: 0.0702 AC: 339 AN: 4832

European-Finnish (FIN) AF: 0.0207 AC: 220 AN: 10620

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0473 AC: 3219 AN: 68018

Other (OTH) AF: 0.0354 AC: 75 AN: 2116

Alfa AF: 0.0431 Hom.: 450

Bravo AF: 0.0319

Asia WGS AF: 0.0270 AC: 96 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.6
DANN	Benign	0.90
PhyloP100		0.69
Mutation Taster		=99/1	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: rs10187; hg19: chr12-108962804;