9-86272042-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030940.4(ISCA1):c.206C>T(p.Thr69Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ISCA1 NM_030940.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.63

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2843346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISCA1	NM_030940.4	c.206C>T	p.Thr69Ile	missense_variant	3/4	ENST00000375991.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISCA1	ENST00000375991.9	c.206C>T	p.Thr69Ile	missense_variant	3/4	1	NM_030940.4	P1
ISCA1	ENST00000637705.1	c.143C>T	p.Thr48Ile	missense_variant	3/4	5
ISCA1	ENST00000326094.4	c.206C>T	p.Thr69Ile	missense_variant	3/4	3
ISCA1	ENST00000311534.6	c.-89C>T		5_prime_UTR_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250110 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000879

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000207 AC: 3 AN: 1452456 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 723146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000677

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 30, 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 tolerated. This variant has not been reported in the literature in individuals affected with ISCA1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 69 of the ISCA1 protein (p.Thr69Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.00025	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D;.;D
REVEL	Benign	0.081
Sift	Uncertain	0.020	D;.;T
Sift4G	Benign	0.061	T;.;T
Polyphen		0.026	B;.;.
Vest4		0.17
MutPred		0.41		Loss of disorder (P = 0.0452);.;Loss of disorder (P = 0.0452);
MVP		0.093
MPC		1.3
ClinPred		0.73	D
GERP RS		5.9
Varity_R		0.18
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs1194713969; hg19: chr9-88886957;