3-149176413-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000096.4(CP):​c.3019-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CP
NM_000096.4 splice_acceptor, intron

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 2.45
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.6, offset of 5, new splice context is: atttttctaattaaacacAGggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-149176413-C-T is Pathogenic according to our data. Variant chr3-149176413-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17559.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.3019-1G>A splice_acceptor_variant, intron_variant Intron 17 of 18 ENST00000264613.11 NP_000087.2 P00450A5PL27

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CPENST00000264613.11 linkc.3019-1G>A splice_acceptor_variant, intron_variant Intron 17 of 18 1 NM_000096.4 ENSP00000264613.6 P00450

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Deficiency of ferroxidase Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 16, 2019For these reasons, this variant has been classified as Pathogenic. This sequence change affects an acceptor splice site in intron 17 of the CP gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with aceruloplasminemia in a family (PMID: 7539672). ClinVar contains an entry for this variant (Variation ID: 17559). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CP are known to be pathogenic (PMID: 16629161). -
Pathogenic, no assertion criteria providedcurationGeneReviewsApr 18, 2013- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 1995- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
32
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Uncertain
0.93
D
GERP RS
5.6

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.90
SpliceAI score (max)
0.29
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.29
Position offset: -6

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: rs386134142; hg19: chr3-148894200; API