Genetic Variant ISCU:p.Phe7Ser (chr12-108562642-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_213595.4(ISCU):c.20T>C(p.Phe7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F7C) has been classified as Benign.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ISCU
NM_213595.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.66

Publications

18 publications found

Variant links:

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

ISCU links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1010775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISCU	NM_213595.4 link	c.20T>C	p.Phe7Ser	missense_variant	Exon 1 of 5	ENST00000311893.14	NP_998760.1	Q9H1K1-1B3KQ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISCU	ENST00000311893.14 link	c.20T>C	p.Phe7Ser	missense_variant	Exon 1 of 5	1	NM_213595.4	ENSP00000310623.9		Q9H1K1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1324910

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

652858

African (AFR)

AF:

0.00

AC:

AN:

27074

American (AMR)

AF:

0.00

AC:

AN:

28394

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22666

East Asian (EAS)

AF:

0.00

AC:

AN:

30416

South Asian (SAS)

AF:

0.00

AC:

AN:

70934

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4532

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1053538

Other (OTH)

AF:

0.00

AC:

AN:

54930

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

2953

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.063

.;T;.;T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.071

.;T;T;T;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.10

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.;N;.

PhyloP100

1.7

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

0.49

N;N;N;N;N

REVEL

Benign

0.21

Sift

Benign

0.40

T;T;T;T;T

Sift4G

Benign

0.41

T;T;T;T;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.27

MutPred

0.34

Gain of phosphorylation at F7 (P = 0.0059);Gain of phosphorylation at F7 (P = 0.0059);Gain of phosphorylation at F7 (P = 0.0059);Gain of phosphorylation at F7 (P = 0.0059);Gain of phosphorylation at F7 (P = 0.0059);

MVP

0.52

MPC

0.62

ClinPred

0.18

GERP RS

5.0

PromoterAI

0.019

Neutral

(source)

Varity_R

0.057

gMVP

0.69

Mutation Taster

=286/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over