rs10187

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-108569028-C-A
• chr12-108569028-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000539580.5(ISCU):​n.*671C>A 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 0.00000586 in 682,858 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: 33)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• Consequence: ISCU ENST00000539580.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.690
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000586 AC: 4 AN: 682858 Hom.: 0 Cov.: 9 AF XY: 0.00000278 AC XY: 1 AN XY: 359812

African (AFR) AF: 0.0000569 AC: 1 AN: 17584

American (AMR) AF: 0.00 AC: 0 AN: 33698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20490

East Asian (EAS) AF: 0.00 AC: 0 AN: 32606

South Asian (SAS) AF: 0.00 AC: 0 AN: 64458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2690

European-Non Finnish (NFE) AF: 0.00000692 AC: 3 AN: 433478

Other (OTH) AF: 0.00 AC: 0 AN: 34446

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.2
DANN	Benign	0.90
PhyloP100		0.69
Mutation Taster		=99/1	polymorphism

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;