16-730569-C-T

Variant names:

• chr16-730569-C-T
• NM_022493.3:c.1279G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022493.3(CIAO3):​c.1279G>A​(p.Val427Ile) 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 1,458,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CIAO3 NM_022493.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11168879).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIAO3	NM_022493.3	c.1279G>A	p.Val427Ile	missense_variant	Exon 11 of 11	ENST00000251588.7	NP_071938.1
CIAO3	NM_001304799.2	c.973G>A	p.Val325Ile	missense_variant	Exon 12 of 12		NP_001291728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIAO3	ENST00000251588.7	c.1279G>A	p.Val427Ile	missense_variant	Exon 11 of 11	1	NM_022493.3	ENSP00000251588.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458668 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725708

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1279G>A (p.V427I) alteration is located in exon 11 (coding exon 11) of the NARFL gene. This alteration results from a G to A substitution at nucleotide position 1279, causing the valine (V) at amino acid position 427 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.061	T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.62	T;.;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.25	N;N;N
REVEL	Benign	0.042
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.043
MutPred		0.30		Loss of disorder (P = 0.128);.;.;
MVP		0.34
MPC		0.13
ClinPred		0.24	T
GERP RS		4.0
Varity_R		0.071
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-780569;