16-730575-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_022493.3(CIAO3):c.1273G>A(p.Gly425Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,611,034 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (6 hom.)
• Consequence: CIAO3 NM_022493.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.40

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004664868).
• BP6: Variant 16-730575-C-T is Benign according to our data. Variant chr16-730575-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 718886.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIAO3	NM_022493.3	c.1273G>A	p.Gly425Ser	missense_variant	11/11	ENST00000251588.7
CIAO3	NM_001304799.2	c.967G>A	p.Gly323Ser	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIAO3	ENST00000251588.7	c.1273G>A	p.Gly425Ser	missense_variant	11/11	1	NM_022493.3	P1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152266 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00179 AC: 443 AN: 247108 Hom.: 0 AF XY: 0.00178 AC XY: 240 AN XY: 134578

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00213

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.00300

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00161 AC: 2355 AN: 1458650 Hom.: 6 Cov.: 32 AF XY: 0.00164 AC XY: 1188 AN XY: 725708

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00164

Gnomad4 SAS exome AF: 0.00239

Gnomad4 FIN exome AF: 0.00262

Gnomad4 NFE exome AF: 0.00162

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152384 Hom.: 1 Cov.: 34 AF XY: 0.00140 AC XY: 104 AN XY: 74520

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00237

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00106

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.00191 AC: 232

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.0070
Dann	Benign	0.87
DEOGEN2	Benign	0.048	T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.34	T;.;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.0047	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.0	N;N;N
REVEL	Benign	0.010
Sift	Benign	0.70	T;T;T
Sift4G	Benign	0.73	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.050
MVP		0.14
MPC		0.16
ClinPred		0.0027	T
GERP RS		-3.7
Varity_R		0.039
gMVP		0.32

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: rs137994770; hg19: chr16-780575;