12-108562644-C-G

Variant names:

• chr12-108562644-C-G
• rs11548233
• NM_213595.4:c.22C>G

Variant summary

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

The NM_213595.4(ISCU):​c.22C>G​(p.Arg8Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ISCU NM_213595.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISCU	NM_213595.4	c.22C>G	p.Arg8Gly	missense_variant	Exon 1 of 5	ENST00000311893.14	NP_998760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISCU	ENST00000311893.14	c.22C>G	p.Arg8Gly	missense_variant	Exon 1 of 5	1	NM_213595.4	ENSP00000310623.9

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1329816 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 656052

African (AFR) AF: 0.00 AC: 0 AN: 27216

American (AMR) AF: 0.00 AC: 0 AN: 28990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22748

East Asian (EAS) AF: 0.00 AC: 0 AN: 30482

South Asian (SAS) AF: 0.00 AC: 0 AN: 71514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32650

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1056398

Other (OTH) AF: 0.00 AC: 0 AN: 55156

GnomAD4 genome Cov.: 36

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 8 of the ISCU protein (p.Arg8Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ISCU-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.094	.;T;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.82	.;T;T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.47	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	.;.;.;N;.
PhyloP100		1.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.011	D;D;D;D;D
Sift4G	Benign	0.32	T;T;T;T;T
Polyphen		0.65	P;P;P;B;P
Vest4		0.36
MutPred		0.33		Loss of methylation at R8 (P = 0.0037);Loss of methylation at R8 (P = 0.0037);Loss of methylation at R8 (P = 0.0037);Loss of methylation at R8 (P = 0.0037);Loss of methylation at R8 (P = 0.0037);
MVP		0.71
MPC		0.45
ClinPred		0.53	D
GERP RS		5.0
PromoterAI		0.045	Neutral
Varity_R		0.24
gMVP		0.67
Mutation Taster		=283/17	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: rs11548233; hg19: chr12-108956420;