16-730664-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_022493.3(CIAO3):c.1193-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,606,160 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0081 (14 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (17 hom.)
• Consequence: CIAO3 NM_022493.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002658
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.36

Genes affected

CIAO3 (HGNC:14179): (cytosolic iron-sulfur assembly component 3) Predicted to enable 4 iron, 4 sulfur cluster binding activity. Involved in several processes, including iron-sulfur cluster assembly; oxygen homeostasis; and response to hypoxia. Part of CIA complex. [provided by Alliance of Genome Resources, Apr 2022]

HAGHL (HGNC:14177): (hydroxyacylglutathione hydrolase like) Predicted to enable hydroxyacylglutathione hydrolase activity and metal ion binding activity. Predicted to be involved in methylglyoxal catabolic process to D-lactate via S-lactoyl-glutathione. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-730664-G-A is Benign according to our data. Variant chr16-730664-G-A is described in ClinVar as [Benign]. Clinvar id is 717459.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00813 (1239/152348) while in subpopulation AFR AF= 0.0268 (1115/41576). AF 95% confidence interval is 0.0255. There are 14 homozygotes in gnomad4. There are 570 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIAO3	NM_022493.3	c.1193-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000251588.7
CIAO3	NM_001304799.2	c.887-9C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIAO3	ENST00000251588.7	c.1193-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_022493.3	P1

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1238 AN: 152230 Hom.: 14 Cov.: 34

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00246 AC: 592 AN: 240466 Hom.: 7 AF XY: 0.00175 AC XY: 231 AN XY: 131984

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00195

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.00108 AC: 1567 AN: 1453812 Hom.: 17 Cov.: 31 AF XY: 0.000936 AC XY: 677 AN XY: 723296

Gnomad4 AFR exome AF: 0.0281

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00410

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00813 AC: 1239 AN: 152348 Hom.: 14 Cov.: 34 AF XY: 0.00765 AC XY: 570 AN XY: 74500

Gnomad4 AFR AF: 0.0268

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00480 Hom.: 4

Bravo AF: 0.00950

Asia WGS AF: 0.00173 AC: 6 AN: 3478

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

Dec 04, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	8.2
Dann	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0027
dbscSNV1_RF	Benign	0.020
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: rs114620274; hg19: chr16-780664;