3-149221646-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_000096.4(CP):​c.146+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000993 in 1,611,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CP
NM_000096.4 splice_donor, intron

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.87
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.057223264 fraction of the gene.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-149221646-C-T is Pathogenic according to our data. Variant chr3-149221646-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42135.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CPNM_000096.4 linkc.146+1G>A splice_donor_variant, intron_variant Intron 1 of 18 ENST00000264613.11 NP_000087.2 P00450A5PL27

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CPENST00000264613.11 linkc.146+1G>A splice_donor_variant, intron_variant Intron 1 of 18 1 NM_000096.4 ENSP00000264613.6 P00450
CPENST00000490639.5 linkn.178+1G>A splice_donor_variant, intron_variant Intron 1 of 16 1
CPENST00000455472.3 linkc.146+1G>A splice_donor_variant, intron_variant Intron 1 of 3 5 ENSP00000426888.1 D6RE86
CPENST00000481169.5 linkn.146+1G>A splice_donor_variant, intron_variant Intron 1 of 17 2 ENSP00000418773.1 E9PFZ2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1459318
Hom.:
0
Cov.:
31
AF XY:
0.00000965
AC XY:
7
AN XY:
725726
show subpopulations
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:
0.0000135
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Deficiency of ferroxidase Pathogenic:1
Apr 18, 2013
GeneReviews
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

- -

not provided Pathogenic:1
Jul 03, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Identified in patients with aceruloplasminemia in published literature; this includes one homozgous patient and one patient with c.146+1G>A and a second CP variant but phase was not known (PMID: 34670377); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14742624, 34670377) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
33
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Uncertain
0.93
D
GERP RS
5.2

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.99
Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386134134; hg19: chr3-148939433; API