9-86266085-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_030940.4(ISCA1):c.348C>T(p.Asn116=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0237 in 1,612,782 control chromosomes in the GnomAD database, including 570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (53 hom., cov: 32)
  • Exomes 𝑓: 0.024 (517 hom.)
• Consequence: ISCA1 NM_030940.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.64

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 9-86266085-G-A is Benign according to our data. Variant chr9-86266085-G-A is described in ClinVar as [Benign]. Clinvar id is 1169189.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.018 (2738/152296) while in subpopulation NFE AF= 0.0259 (1764/68014). AF 95% confidence interval is 0.0249. There are 53 homozygotes in gnomad4. There are 1239 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISCA1	NM_030940.4	c.348C>T	p.Asn116=	synonymous_variant	4/4	ENST00000375991.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISCA1	ENST00000375991.9	c.348C>T	p.Asn116=	synonymous_variant	4/4	1	NM_030940.4	P1
ISCA1	ENST00000311534.6	c.54C>T	p.Asn18=	synonymous_variant	4/4	2
ISCA1	ENST00000637705.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2735 AN: 152178 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00574

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0859

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0193 AC: 4742 AN: 245338 Hom.: 77 AF XY: 0.0197 AC XY: 2623 AN XY: 132934

Gnomad AFR exome AF: 0.00490

Gnomad AMR exome AF: 0.0149

Gnomad ASJ exome AF: 0.0791

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00814

Gnomad FIN exome AF: 0.00386

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0236

GnomAD4 exome AF: 0.0243 AC: 35453 AN: 1460486 Hom.: 517 Cov.: 31 AF XY: 0.0241 AC XY: 17528 AN XY: 726516

Gnomad4 AFR exome AF: 0.00520

Gnomad4 AMR exome AF: 0.0166

Gnomad4 ASJ exome AF: 0.0791

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00877

Gnomad4 FIN exome AF: 0.00408

Gnomad4 NFE exome AF: 0.0266

Gnomad4 OTH exome AF: 0.0283

GnomAD4 genome AF: 0.0180 AC: 2738 AN: 152296 Hom.: 53 Cov.: 32 AF XY: 0.0166 AC XY: 1239 AN XY: 74486

Gnomad4 AFR AF: 0.00573

Gnomad4 AMR AF: 0.0170

Gnomad4 ASJ AF: 0.0859

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00745

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.0259

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0303 Hom.: 32

Bravo AF: 0.0198

EpiCase AF: 0.0325

EpiControl AF: 0.0297

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	6.4
Dann	Benign	0.83

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: rs61743948; hg19: chr9-88881000; COSMIC: COSV58181823; COSMIC: COSV58181823;