rs386134143

Positions:

• chr3-149210167-C-CT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000096.4(CP):​c.606dupA​(p.Asp203fs) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CP NM_000096.4 frameshift, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.79

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 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 3-149210167-C-CT is Pathogenic according to our data. Variant chr3-149210167-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 17563.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CP	NM_000096.4	c.606dupA	p.Asp203fs	frameshift_variant, splice_region_variant	3/19	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11	c.606dupA	p.Asp203fs	frameshift_variant, splice_region_variant	3/19	1	NM_000096.4	ENSP00000264613.6
CP	ENST00000490639.5	n.638dupA		splice_region_variant, non_coding_transcript_exon_variant	3/17	1
CP	ENST00000481169.5	n.606dupA		splice_region_variant, non_coding_transcript_exon_variant	3/18	2		ENSP00000418773.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461556 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727084

Gnomad4 AFR exome AF: 0.0000299

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Deficiency of ferroxidase Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1996	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 18, 2013	- -

Computational scores

Source: dbNSFP v4.3

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: rs386134143; hg19: chr3-148927954;