rs880844

Positions:

• chr12-108568592-G-A
• chr12-108568592-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000311893.14(ISCU):​c.419-239G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,391,868 control chromosomes in the GnomAD database, including 47,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3870 hom., cov: 32)
  • Exomes 𝑓: 0.26 (43395 hom.)
• Consequence: ISCU ENST00000311893.14 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.198

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-108568592-G-A is Benign according to our data. Variant chr12-108568592-G-A is described in ClinVar as [Benign]. Clinvar id is 681977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ISCU	NM_213595.4	c.419-239G>A		intron_variant		ENST00000311893.14	NP_998760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ISCU	ENST00000311893.14	c.419-239G>A		intron_variant		1	NM_213595.4	ENSP00000310623	P1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30283 AN: 152064 Hom.: 3870 Cov.: 32

Gnomad AFR AF: 0.0473

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.205

GnomAD4 exome AF: 0.258 AC: 319501 AN: 1239686 Hom.: 43395 Cov.: 28 AF XY: 0.261 AC XY: 156373 AN XY: 600028

Gnomad4 AFR exome AF: 0.0393

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.490

Gnomad4 SAS exome AF: 0.336

Gnomad4 FIN exome AF: 0.296

Gnomad4 NFE exome AF: 0.253

Gnomad4 OTH exome AF: 0.257

GnomAD4 genome AF: 0.199 AC: 30283 AN: 152182 Hom.: 3870 Cov.: 32 AF XY: 0.205 AC XY: 15273 AN XY: 74386

Gnomad4 AFR AF: 0.0472

Gnomad4 AMR AF: 0.180

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.493

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.296

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.205

Alfa AF: 0.239 Hom.: 2102

Bravo AF: 0.184

Asia WGS AF: 0.400 AC: 1389 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.61

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: rs880844; hg19: chr12-108962368;