rs386134121

chr3-149221711-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000096.4(CP):c.82A>T(p.Ile28Phe) variant causes a missense change. 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: CP NM_000096.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.45

Genes affected

CP (HGNC:2295): (ceruloplasmin) The protein encoded by this gene is a metalloprotein that binds most of the copper in plasma and is involved in the peroxidation of Fe(II)transferrin to Fe(III) transferrin. Mutations in this gene cause aceruloplasminemia, which results in iron accumulation and tissue damage, and is associated with diabetes and neurologic abnormalities. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CP	NM_000096.4	c.82A>T	p.Ile28Phe	missense_variant	1/19	ENST00000264613.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CP	ENST00000264613.11	c.82A>T	p.Ile28Phe	missense_variant	1/19	1	NM_000096.4	P1
CP	ENST00000490639.5	n.114A>T		non_coding_transcript_exon_variant	1/17	1
CP	ENST00000455472.3	c.82A>T	p.Ile28Phe	missense_variant	1/4	5
CP	ENST00000481169.5	c.82A>T	p.Ile28Phe	missense_variant, NMD_transcript_variant	1/18	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of ferroxidase Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 18, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 29, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 28 of the CP protein (p.Ile28Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypoceruloplasminemia (PMID: 10997552). This variant is also known as I9F. ClinVar contains an entry for this variant (Variation ID: 42057). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CP protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CP function (PMID: 16775387, 19095659). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;.
Vest4		0.84
MutPred		0.85		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.98
MPC		0.62
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.96

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: rs386134121; hg19: chr3-148939498;