16-730575-C-G

Variant names:

• chr16-730575-C-G
• rs137994770
• NM_022493.3:c.1273G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022493.3(CIAO3):​c.1273G>C​(p.Gly425Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G425S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CIAO3 NM_022493.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 0 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04737383).

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.1273G>C	p.Gly425Arg	missense	Exon 11 of 11	NP_071938.1	Q9H6Q4-1
	CIAO3	NM_001304799.2		c.967G>C	p.Gly323Arg	missense	Exon 12 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.1273G>C	p.Gly425Arg	missense	Exon 11 of 11	ENSP00000251588.2	Q9H6Q4-1
	CIAO3	ENST00000562862.5	TSL:1	n.1189G>C		non_coding_transcript_exon	Exon 6 of 6
	CIAO3	ENST00000946067.1		c.1297G>C	p.Gly433Arg	missense	Exon 12 of 12	ENSP00000616126.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458650 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725708

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111954

Other (OTH) AF: 0.0000166 AC: 1 AN: 60354

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.0040
DANN	Benign	0.70
DEOGEN2	Benign	0.048	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.0070
Sift	Benign	0.57	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.084
MutPred		0.43		Gain of MoRF binding (P = 0.0161)
MVP		0.14
MPC		0.20
ClinPred		0.029	T
GERP RS		-3.7
Varity_R		0.076
gMVP		0.39

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

Other links and lift over

dbSNP: rs137994770; hg19: chr16-780575;