12-108562641-T-G

Position:

• chr12-108562641-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_213595.4(ISCU):​c.19T>G​(p.Phe7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.876 in 1,468,804 control chromosomes in the GnomAD database, including 564,017 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F7C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.86 (56937 hom., cov: 36)
  • Exomes 𝑓: 0.88 (507080 hom.)
• Consequence: ISCU NM_213595.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.46

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.0388344E-7).
• BP6: Variant 12-108562641-T-G is Benign according to our data. Variant chr12-108562641-T-G is described in ClinVar as [Benign]. Clinvar id is 768575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-108562641-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISCU	NM_213595.4	c.19T>G	p.Phe7Val	missense_variant	1/5	ENST00000311893.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISCU	ENST00000311893.14	c.19T>G	p.Phe7Val	missense_variant	1/5	1	NM_213595.4	P1

Frequencies

GnomAD3 genomes AF: 0.865 AC: 131379 AN: 151914 Hom.: 56880 Cov.: 36

Gnomad AFR AF: 0.832

Gnomad AMI AF: 0.873

Gnomad AMR AF: 0.867

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.932

Gnomad FIN AF: 0.843

Gnomad MID AF: 0.885

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.854

GnomAD3 exomes AF: 0.864 AC: 84714 AN: 98058 Hom.: 36757 AF XY: 0.866 AC XY: 49154 AN XY: 56754

Gnomad AFR exome AF: 0.780

Gnomad AMR exome AF: 0.848

Gnomad ASJ exome AF: 0.878

Gnomad EAS exome AF: 0.916

Gnomad SAS exome AF: 0.915

Gnomad FIN exome AF: 0.825

Gnomad NFE exome AF: 0.853

Gnomad OTH exome AF: 0.852

GnomAD4 exome AF: 0.877 AC: 1154596 AN: 1316774 Hom.: 507080 Cov.: 33 AF XY: 0.878 AC XY: 569976 AN XY: 649020

Gnomad4 AFR exome AF: 0.836

Gnomad4 AMR exome AF: 0.859

Gnomad4 ASJ exome AF: 0.888

Gnomad4 EAS exome AF: 0.941

Gnomad4 SAS exome AF: 0.925

Gnomad4 FIN exome AF: 0.847

Gnomad4 NFE exome AF: 0.874

Gnomad4 OTH exome AF: 0.880

GnomAD4 genome AF: 0.865 AC: 131495 AN: 152030 Hom.: 56937 Cov.: 36 AF XY: 0.865 AC XY: 64277 AN XY: 74318

Gnomad4 AFR AF: 0.832

Gnomad4 AMR AF: 0.867

Gnomad4 ASJ AF: 0.895

Gnomad4 EAS AF: 0.938

Gnomad4 SAS AF: 0.931

Gnomad4 FIN AF: 0.843

Gnomad4 NFE AF: 0.876

Gnomad4 OTH AF: 0.856

Alfa AF: 0.870 Hom.: 9535

Bravo AF: 0.864

ExAC AF: 0.844 AC: 83727

Asia WGS AF: 0.944 AC: 3256 AN: 3450

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -

Hereditary myopathy with lactic acidosis due to ISCU deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Benign	0.64
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.00089	N
MetaRNN	Benign	8.0e-7	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.18	N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.52	T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.20
MPC		0.46
ClinPred		0.042	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.055
gMVP		0.62

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: rs10778647; hg19: chr12-108956417; COSMIC: COSV57206465; COSMIC: COSV57206465;