chr2-96267331-G-T

Variant names:

• chr2-96267331-G-T
• rs1350699132
• NM_004804.3:c.150G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004804.3(CIAO1):​c.150G>T​(p.Trp50Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CIAO1 NM_004804.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34
• Publications: 0 publications found

Genes affected

CIAO1 (HGNC:14280): (cytosolic iron-sulfur assembly component 1) Involved in iron-sulfur cluster assembly and protein maturation by iron-sulfur cluster transfer. Located in cytoplasm. Part of CIA complex and MMXD complex. [provided by Alliance of Genome Resources, Apr 2022]

CIAO1 Gene-Disease associations (from GenCC):

• multiple mitochondrial dysfunctions syndrome 10

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIAO1	NM_004804.3	c.150G>T	p.Trp50Cys	missense_variant	Exon 2 of 7	ENST00000488633.2	NP_004795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIAO1	ENST00000488633.2	c.150G>T	p.Trp50Cys	missense_variant	Exon 2 of 7	1	NM_004804.3	ENSP00000418287.1
CIAO1	ENST00000469320.1	n.373G>T		non_coding_transcript_exon_variant	Exon 2 of 3	4
CIAO1	ENST00000491394.1	n.255G>T		non_coding_transcript_exon_variant	Exon 2 of 3	2
CIAO1	ENST00000272402.2	n.250-294G>T		intron_variant	Intron 1 of 4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.150G>T (p.W50C) alteration is located in exon 2 (coding exon 2) of the CIAO1 gene. This alteration results from a G to T substitution at nucleotide position 150, causing the tryptophan (W) at amino acid position 50 to be replaced by a cysteine (C). 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	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-11	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.59		Loss of MoRF binding (P = 0.0454);
MVP		0.66
MPC		1.4
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.59
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1350699132; hg19: chr2-96933069;