NM_000096.4:c.2630G>A

Variant names:

• chr3-149179587-C-T
• rs121909579
• NM_000096.4:c.2630G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000096.4(CP):​c.2630G>A​(p.Trp877*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CP NM_000096.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 2.92
• Publications: 5 publications found

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]

CP Gene-Disease associations (from GenCC):

• aceruloplasminemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• disorder of iron metabolism and transport

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-149179587-C-T is Pathogenic according to our data. Variant chr3-149179587-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17562.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000096.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	NM_000096.4	MANE Select	c.2630G>A	p.Trp877*	stop_gained	Exon 15 of 19	NP_000087.2
	CP	NR_046371.2		n.2454G>A		non_coding_transcript_exon	Exon 14 of 18

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.2630G>A	p.Trp877*	stop_gained	Exon 15 of 19	ENSP00000264613.6
	CP	ENST00000494544.1	TSL:1	c.1979G>A	p.Trp660*	stop_gained	Exon 12 of 16	ENSP00000420545.1
	CP	ENST00000460674.5	TSL:1	n.547G>A		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251326 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of ferroxidase Pathogenic:2

Apr 18, 2013

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Dec 26, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Jul 19, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The W877X variant in the CP gene has been reported previously in trans with another CP variant in two siblings with aceruloplasminemia (Kin et al., 2017). This variant has also been reported previously in the heterozygous state, as Trp858ter due to the use of alternate nomenclature, in multiple unrelated patients with aceruloplasminemia and associated symptoms for whom no second CP variant was identified (Daimon et al., 1995; Nakane et al., 1999; Miyajima et al., 2001; Matsushima et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In vitro assays of W877X demonstrate this variant exhibits protein synthesis identical to wild-type; however, the mutant protein is retained within the endoplasmic reticulum (Kono et al., 2007). The W877X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret W877X as a pathogenic variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Benign	0.75	D
PhyloP100		2.9
Vest4		0.93
GERP RS		5.7
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121909579; hg19: chr3-148897374;