chr12-108562652-G-C

Variant names:

• chr12-108562652-G-C
• rs776009693
• NM_213595.4:c.30G>C

Variant summary

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

The NM_213595.4(ISCU):​c.30G>C​(p.Arg10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,309,372 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R10K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 37)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: ISCU NM_213595.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0500
• 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 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.30G>C	p.Arg10Ser	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.30G>C	p.Arg10Ser	missense_variant	Exon 1 of 5	1	NM_213595.4	ENSP00000310623.9

Frequencies

GnomAD3 genomes Cov.: 37

GnomAD2 exomes AF: 0.00 AC: 0 AN: 76830 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.64e-7 AC: 1 AN: 1309372 Hom.: 0 Cov.: 35 AF XY: 0.00000155 AC XY: 1 AN XY: 643902

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26664

American (AMR) AF: 0.00 AC: 0 AN: 26822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21792

East Asian (EAS) AF: 0.00 AC: 0 AN: 29544

South Asian (SAS) AF: 0.0000145 AC: 1 AN: 68796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1045088

Other (OTH) AF: 0.00 AC: 0 AN: 54416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 37

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.087	.;T;.;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.85	.;T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.55	D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	.;.;.;N;.
PhyloP100		0.050
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.68	N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.091	T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T
Polyphen		0.97	D;D;D;P;D
Vest4		0.57
MutPred		0.34		Loss of methylation at R10 (P = 0.007);Loss of methylation at R10 (P = 0.007);Loss of methylation at R10 (P = 0.007);Loss of methylation at R10 (P = 0.007);Loss of methylation at R10 (P = 0.007);
MVP		0.67
MPC		0.39
ClinPred		0.28	T
GERP RS		1.4
PromoterAI		0.013	Neutral
Varity_R		0.093
gMVP		0.75
Mutation Taster		=87/13	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: rs776009693; hg19: chr12-108956428;