chr12-108562644-C-G

Position:

• chr12-108562644-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/21 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

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISCU	NM_213595.4	c.22C>G	p.Arg8Gly	missense_variant	1/5	ENST00000311893.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISCU	ENST00000311893.14	c.22C>G	p.Arg8Gly	missense_variant	1/5	1	NM_213595.4	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 36

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 27, 2022

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
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.039	N
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.47	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.95	D;D;D;D;D;D;D
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
Varity_R		0.24
gMVP		0.67

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: rs11548233; hg19: chr12-108956420;