9-86274233-C-T

Position:

• chr9-86274233-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030940.4(ISCA1):​c.91G>A​(p.Ala31Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ISCA1 NM_030940.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.96

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ISCA1	NM_030940.4	c.91G>A	p.Ala31Thr	missense_variant	2/4	ENST00000375991.9	NP_112202.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ISCA1	ENST00000375991.9	c.91G>A	p.Ala31Thr	missense_variant	2/4	1	NM_030940.4	ENSP00000365159	P1
ISCA1	ENST00000637705.1	c.28G>A	p.Ala10Thr	missense_variant	2/4	5		ENSP00000489740
ISCA1	ENST00000326094.4	c.91G>A	p.Ala31Thr	missense_variant	2/4	3		ENSP00000365157
ISCA1	ENST00000311534.6	c.-204G>A		5_prime_UTR_variant	2/4	2		ENSP00000339003

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1434836 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 715532

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 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 variant has not been reported in the literature in individuals affected with ISCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 31 of the ISCA1 protein (p.Ala31Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	5.0	H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.7	D;.;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.85
MutPred		0.88		Gain of phosphorylation at A31 (P = 0.0632);.;Gain of phosphorylation at A31 (P = 0.0632);
MVP		0.47
MPC		1.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.76
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-88889148;