rs147538611

Variant names:

• chr16-730942-C-A
• rs147538611
• NM_022493.3:c.1093G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-730942-C-A
• chr16-730942-C-T
• chr16-730942-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022493.3(CIAO3):​c.1093G>T​(p.Ala365Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A365T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CIAO3 NM_022493.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45
• Publications: 3 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022493.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIAO3	NM_022493.3	MANE Select	c.1093G>T	p.Ala365Ser	missense	Exon 10 of 11	NP_071938.1	Q9H6Q4-1
	CIAO3	NM_001304799.2		c.787G>T	p.Ala263Ser	missense	Exon 11 of 12	NP_001291728.1	Q9H6Q4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIAO3	ENST00000251588.7	TSL:1 MANE Select	c.1093G>T	p.Ala365Ser	missense	Exon 10 of 11	ENSP00000251588.2	Q9H6Q4-1
	CIAO3	ENST00000562862.5	TSL:1	n.1009G>T		non_coding_transcript_exon	Exon 5 of 6
	CIAO3	ENST00000946067.1		c.1117G>T	p.Ala373Ser	missense	Exon 11 of 12	ENSP00000616126.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250676 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460626 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726604

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	-0.040	T
PhyloP100		7.4
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.80		Loss of catalytic residue at M366 (P = 0.0247)
MVP		0.55
MPC		0.66
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.60
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147538611; hg19: chr16-780942;