12-108562649-G-T

Variant names:

• chr12-108562649-G-T
• rs11837563
• NM_213595.4:c.27G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_213595.4(ISCU):​c.27G>T​(p.Leu9Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,461,504 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L9L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.027 (200 hom., cov: 36)
  • Exomes 𝑓: 0.0024 (154 hom.)
• Consequence: ISCU NM_213595.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.07
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 12-108562649-G-T is Benign according to our data. Variant chr12-108562649-G-T is described in ClinVar as Benign. ClinVar VariationId is 137593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0932 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213595.4. 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.27G>T	p.Leu9Leu	synonymous	Exon 1 of 5	NP_998760.1	Q9H1K1-1
	ISCU	NM_001301141.1		c.27G>T	p.Leu9Leu	synonymous	Exon 1 of 6	NP_001288070.1	B3KQ30
	ISCU	NM_001301140.1		c.27G>T	p.Leu9Leu	synonymous	Exon 1 of 6	NP_001288069.1	B3KQ30

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISCU	ENST00000311893.14	TSL:1 MANE Select	c.27G>T	p.Leu9Leu	synonymous	Exon 1 of 5	ENSP00000310623.9	Q9H1K1-1
	ISCU	ENST00000392807.8	TSL:1	c.-145G>T		5_prime_UTR	Exon 1 of 6	ENSP00000376554.4	Q9H1K1-2
	ISCU	ENST00000539580.5	TSL:1	n.27G>T		non_coding_transcript_exon	Exon 1 of 7	ENSP00000437854.1	F5H672

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4157 AN: 152182 Hom.: 199 Cov.: 36

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00791

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00610 AC: 466 AN: 76374 AF XY: 0.00518

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00447

GnomAD4 exome AF: 0.00237 AC: 3105 AN: 1309210 Hom.: 154 Cov.: 34 AF XY: 0.00201 AC XY: 1295 AN XY: 643840

African (AFR) AF: 0.0963 AC: 2572 AN: 26702

American (AMR) AF: 0.00480 AC: 128 AN: 26660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21854

East Asian (EAS) AF: 0.00 AC: 0 AN: 29478

South Asian (SAS) AF: 0.000203 AC: 14 AN: 68944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31528

Middle Eastern (MID) AF: 0.00191 AC: 9 AN: 4708

European-Non Finnish (NFE) AF: 0.0000938 AC: 98 AN: 1044932

Other (OTH) AF: 0.00522 AC: 284 AN: 54404

GnomAD4 genome AF: 0.0273 AC: 4159 AN: 152294 Hom.: 200 Cov.: 36 AF XY: 0.0262 AC XY: 1951 AN XY: 74470

African (AFR) AF: 0.0957 AC: 3977 AN: 41566

American (AMR) AF: 0.00790 AC: 121 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68004

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.00366 Hom.: 3

Bravo AF: 0.0305

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.1
DANN	Benign	0.85
PhyloP100		1.1
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=298/2	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: rs11837563; hg19: chr12-108956425;