9-86266185-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030940.4(ISCA1):c.248G>A(p.Arg83Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000265 in 1,604,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R83S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: ISCA1 NM_030940.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0702956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISCA1	NM_030940.4	c.248G>A	p.Arg83Lys	missense_variant	4/4	ENST00000375991.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISCA1	ENST00000375991.9	c.248G>A	p.Arg83Lys	missense_variant	4/4	1	NM_030940.4	P1
ISCA1	ENST00000637705.1	c.185G>A	p.Arg62Lys	missense_variant	4/4	5
ISCA1	ENST00000311534.6	c.-47G>A		5_prime_UTR_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000212 AC: 51 AN: 240210 Hom.: 0 AF XY: 0.000224 AC XY: 29 AN XY: 129680

Gnomad AFR exome AF: 0.000250

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: 0.0000467

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000273 AC: 396 AN: 1452288 Hom.: 0 Cov.: 31 AF XY: 0.000254 AC XY: 183 AN XY: 721784

Gnomad4 AFR exome AF: 0.000183

Gnomad4 AMR exome AF: 0.0000707

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000938

Gnomad4 NFE exome AF: 0.000337

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74496

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000291 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000593

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

May 31, 2022

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 83 of the ISCA1 protein (p.Arg83Lys). This variant is present in population databases (rs140944675, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ISCA1-related conditions. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	18
Dann	Benign	0.71
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.24	N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.080	N;.
REVEL	Benign	0.053
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;.
Vest4		0.18
MVP		0.093
MPC		0.80
ClinPred		0.047	T
GERP RS		4.8
Varity_R		0.19
gMVP		0.77

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: rs140944675; hg19: chr9-88881100;