Variant 9-86266116-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_030940.4(ISCA1):c.317T>C(p.Leu106Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ISCA1
NM_030940.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.95

Variant links:

Genes affected

ISCA1 (HGNC:28660): (iron-sulfur cluster assembly 1) ISCA1 is a mitochondrial protein involved in the biogenesis and assembly of iron-sulfur clusters, which play a role in electron-transfer reactions (Cozar-Castellano et al., 2004 [PubMed 15262227]).[supplied by OMIM, Mar 2008]

ISCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ISCA1	NM_030940.4 linkuse as main transcript	c.317T>C	p.Leu106Ser	missense_variant	4/4	ENST00000375991.9	NP_112202.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ISCA1	ENST00000375991.9 linkuse as main transcript	c.317T>C	p.Leu106Ser	missense_variant	4/4	1	NM_030940.4	ENSP00000365159	P1	Q9BUE6-1
ISCA1	ENST00000637705.1 linkuse as main transcript	c.254T>C	p.Leu85Ser	missense_variant	4/4	5		ENSP00000489740
ISCA1	ENST00000311534.6 linkuse as main transcript	c.23T>C	p.Leu8Ser	missense_variant	4/4	2		ENSP00000339003

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

245860

Hom.:

AF XY:

0.0000226

AC XY:

AN XY:

132952

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000929

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460934

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726730

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 07, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 106 of the ISCA1 protein (p.Leu106Ser). This variant is present in population databases (rs772282632, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with ISCA1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.;.

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

3.2

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.7

D;D;.

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

0.99

D;.;.

Vest4

0.69

MutPred

0.70

Gain of disorder (P = 0.002);.;.;

MVP

0.35

MPC

2.2

ClinPred

0.99

GERP RS

5.7

Varity_R

0.86

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over