rs10778648

Variant names:

• chr12-108562642-T-G
• rs10778648
• ENST00000392807.8:c.-152T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-108562642-T-G
• chr12-108562642-T-A
• chr12-108562642-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014301.4(ISCU):​c.-152T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.876 in 1,469,126 control chromosomes in the GnomAD database, including 563,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56936 hom., cov: 35)
  • Exomes 𝑓: 0.88 (507051 hom.)
• Consequence: ISCU NM_014301.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.66
• Publications: 18 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.985378E-7).
• BP6: Variant 12-108562642-T-G is Benign according to our data. Variant chr12-108562642-T-G is described in ClinVar as Benign. ClinVar VariationId is 559221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014301.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISCU	NM_213595.4	MANE Select	c.20T>G	p.Phe7Cys	missense	Exon 1 of 5	NP_998760.1	Q9H1K1-1
	ISCU	NM_014301.4		c.-152T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_055116.1	Q9H1K1-2
	ISCU	NM_001301141.1		c.20T>G	p.Phe7Cys	missense	Exon 1 of 6	NP_001288070.1	B3KQ30

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISCU	ENST00000392807.8	TSL:1	c.-152T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000376554.4	Q9H1K1-2
	ISCU	ENST00000311893.14	TSL:1 MANE Select	c.20T>G	p.Phe7Cys	missense	Exon 1 of 5	ENSP00000310623.9	Q9H1K1-1
	ISCU	ENST00000392807.8	TSL:1	c.-152T>G		5_prime_UTR	Exon 1 of 6	ENSP00000376554.4	Q9H1K1-2

Frequencies

GnomAD3 genomes AF: 0.865 AC: 131377 AN: 151912 Hom.: 56879 Cov.: 35

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

GnomAD2 exomes AF: 0.863 AC: 84642 AN: 98032 AF XY: 0.865

Gnomad AFR exome AF: 0.777

Gnomad AMR exome AF: 0.848

Gnomad ASJ exome AF: 0.877

Gnomad EAS exome AF: 0.917

Gnomad FIN exome AF: 0.825

Gnomad NFE exome AF: 0.852

Gnomad OTH exome AF: 0.852

GnomAD4 exome AF: 0.877 AC: 1154731 AN: 1317098 Hom.: 507051 Cov.: 33 AF XY: 0.878 AC XY: 570016 AN XY: 649158

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

African (AFR) AF: 0.836 AC: 22524 AN: 26940

American (AMR) AF: 0.859 AC: 24098 AN: 28048

Ashkenazi Jewish (ASJ) AF: 0.888 AC: 20021 AN: 22540

East Asian (EAS) AF: 0.941 AC: 28589 AN: 30378

South Asian (SAS) AF: 0.925 AC: 65280 AN: 70610

European-Finnish (FIN) AF: 0.847 AC: 27401 AN: 32360

Middle Eastern (MID) AF: 0.886 AC: 3998 AN: 4514

European-Non Finnish (NFE) AF: 0.874 AC: 914678 AN: 1047022

Other (OTH) AF: 0.880 AC: 48142 AN: 54686

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.865 AC: 131493 AN: 152028 Hom.: 56936 Cov.: 35 AF XY: 0.865 AC XY: 64267 AN XY: 74308

African (AFR) AF: 0.832 AC: 34525 AN: 41472

American (AMR) AF: 0.868 AC: 13278 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 3106 AN: 3472

East Asian (EAS) AF: 0.938 AC: 4834 AN: 5152

South Asian (SAS) AF: 0.931 AC: 4499 AN: 4830

European-Finnish (FIN) AF: 0.843 AC: 8914 AN: 10574

Middle Eastern (MID) AF: 0.883 AC: 256 AN: 290

European-Non Finnish (NFE) AF: 0.876 AC: 59487 AN: 67918

Other (OTH) AF: 0.856 AC: 1807 AN: 2112

Alfa AF: 0.844 Hom.: 2953

Bravo AF: 0.864

ExAC AF: 0.844 AC: 83728

Asia WGS AF: 0.944 AC: 3256 AN: 3450

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Hereditary myopathy with lactic acidosis due to ISCU deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Benign	0.77
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.070	T
MetaRNN	Benign	8.0e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.21
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.0030	B
Vest4		0.12
MPC		0.50
ClinPred		0.041	T
GERP RS		5.0
PromoterAI		-0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.66
Mutation Taster		=286/14	polymorphism (auto)

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: rs10778648; hg19: chr12-108956418; COSMIC: COSV57206471; COSMIC: COSV57206471;