12-108569028-C-T

Position:

• chr12-108569028-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_213595.4(ISCU):​c.*112C>T variant causes a 3 prime UTR 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 NM_213595.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.690

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ISCU	NM_213595.4	c.*112C>T		3_prime_UTR_variant	5/5	ENST00000311893.14	NP_998760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ISCU	ENST00000311893.14	c.*112C>T		3_prime_UTR_variant	5/5	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

Gnomad4 AFR exome AF: 0.00944

Gnomad4 AMR exome AF: 0.0376

Gnomad4 ASJ exome AF: 0.0692

Gnomad4 EAS exome AF: 0.00224

Gnomad4 SAS exome AF: 0.0777

Gnomad4 FIN exome AF: 0.0250

Gnomad4 NFE exome AF: 0.0462

Gnomad4 OTH exome AF: 0.0424

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

Gnomad4 AFR AF: 0.00767

Gnomad4 AMR AF: 0.0353

Gnomad4 ASJ AF: 0.0730

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.0702

Gnomad4 FIN AF: 0.0207

Gnomad4 NFE AF: 0.0473

Gnomad4 OTH AF: 0.0354

Alfa AF: 0.0446 Hom.: 215

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs10187; hg19: chr12-108962804;