rs1343944229

Variant names:

• chr12-108562604-G-T
• rs1343944229
• NM_213595.4:c.-19G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-108562604-G-T
• chr12-108562604-G-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_213595.4(ISCU):​c.-19G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000569 in 1,404,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ISCU NM_213595.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.33
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-108562604-G-T is Benign according to our data. Variant chr12-108562604-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 509832.Status of the report is criteria_provided_single_submitter, 1 stars.

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.-19G>T		5_prime_UTR	Exon 1 of 5	NP_998760.1	Q9H1K1-1
	ISCU	NM_001301141.1		c.-19G>T		5_prime_UTR	Exon 1 of 6	NP_001288070.1	B3KQ30
	ISCU	NM_001301140.1		c.-19G>T		5_prime_UTR	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.-19G>T		5_prime_UTR	Exon 1 of 5	ENSP00000310623.9	Q9H1K1-1
	ISCU	ENST00000948249.1		c.-19G>T		5_prime_UTR	Exon 1 of 5	ENSP00000618308.1
	ISCU	ENST00000431221.6	TSL:2	c.-19G>T		5_prime_UTR	Exon 1 of 6	ENSP00000411108.2	B3KQ30

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 6 AN: 1252534 Hom.: 0 Cov.: 20 AF XY: 0.00000649 AC XY: 4 AN XY: 616056

African (AFR) AF: 0.00 AC: 0 AN: 25722

American (AMR) AF: 0.000209 AC: 5 AN: 23896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20946

East Asian (EAS) AF: 0.00 AC: 0 AN: 29098

South Asian (SAS) AF: 0.00 AC: 0 AN: 64990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3980

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1000550

Other (OTH) AF: 0.0000191 AC: 1 AN: 52314

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.000131 AC: 2 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.84
PhyloP100		2.3
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1343944229; hg19: chr12-108956380;