12-108562636-G-A

Variant names:

• chr12-108562636-G-A
• rs587780954
• NM_213595.4:c.14G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_213595.4(ISCU):​c.14G>A​(p.Gly5Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000753 in 1,327,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G5A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: ISCU NM_213595.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.43
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30486932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISCU	NM_213595.4	c.14G>A	p.Gly5Glu	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.14G>A	p.Gly5Glu	missense_variant	Exon 1 of 5	1	NM_213595.4	ENSP00000310623.9

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 7.53e-7 AC: 1 AN: 1327290 Hom.: 0 Cov.: 28 AF XY: 0.00000153 AC XY: 1 AN XY: 654266

⚠️ 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: 27212

American (AMR) AF: 0.00 AC: 0 AN: 28670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22768

East Asian (EAS) AF: 0.00 AC: 0 AN: 30548

South Asian (SAS) AF: 0.00 AC: 0 AN: 71172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4590

European-Non Finnish (NFE) AF: 9.48e-7 AC: 1 AN: 1054614

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

⚠️ 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.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.073	.;T;.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.039
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.82	.;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	.;.;.;N;.
PhyloP100		2.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.91	N;N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.29	B;B;B;B;B
Vest4		0.50
MutPred		0.41		Loss of catalytic residue at A4 (P = 0.0306);Loss of catalytic residue at A4 (P = 0.0306);Loss of catalytic residue at A4 (P = 0.0306);Loss of catalytic residue at A4 (P = 0.0306);Loss of catalytic residue at A4 (P = 0.0306);
MVP		0.70
MPC		0.45
ClinPred		0.71	D
GERP RS		4.0
PromoterAI		0.080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.66
Mutation Taster		=267/33	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: rs587780954; hg19: chr12-108956412;