rs561720120

Variant names:

• chr12-108562647-C-A
• rs561720120
• ENST00000392807.8:c.-147C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-108562647-C-A
• chr12-108562647-C-G
• chr12-108562647-C-T

Variant summary

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

The ENST00000392807.8(ISCU):​c.-147C>A 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 0.00000305 in 1,311,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 37)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: ISCU ENST00000392807.8 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.126
• 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: 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=0.3339595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISCU	NM_213595.4	c.25C>A	p.Leu9Met	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.25C>A	p.Leu9Met	missense_variant	Exon 1 of 5	1	NM_213595.4	ENSP00000310623.9

Frequencies

GnomAD3 genomes Cov.: 37

GnomAD4 exome AF: 0.00000305 AC: 4 AN: 1311134 Hom.: 0 Cov.: 35 AF XY: 0.00000465 AC XY: 3 AN XY: 644932

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

African (AFR) AF: 0.0000375 AC: 1 AN: 26658

American (AMR) AF: 0.00 AC: 0 AN: 26816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22016

East Asian (EAS) AF: 0.00 AC: 0 AN: 29550

South Asian (SAS) AF: 0.00 AC: 0 AN: 69430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4692

European-Non Finnish (NFE) AF: 0.00000287 AC: 3 AN: 1045794

Other (OTH) AF: 0.00 AC: 0 AN: 54468

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.009211), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 37

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.0046	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.071	.;T;.;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.59	.;T;T;T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	.;.;.;N;.
PhyloP100		-0.13
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.56	N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.062	T;T;T;T;T
Sift4G	Benign	0.092	T;T;T;T;T
Polyphen		0.99	D;D;D;D;D
Vest4		0.49
MutPred		0.33		Loss of stability (P = 0.2327);Loss of stability (P = 0.2327);Loss of stability (P = 0.2327);Loss of stability (P = 0.2327);Loss of stability (P = 0.2327);
MVP		0.56
MPC		0.34
ClinPred		0.30	T
GERP RS		2.3
PromoterAI		-0.0034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.44
Mutation Taster		=89/11	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: rs561720120; hg19: chr12-108956423;