chr3-149186167-ATGAAAAGTTTAGGTGCAGAATATTTATGGGAGTCATTCCCCTTCTAGTCTGATTTTCCAGCTATCTTTAAAAGGACCATAATCTAAAAAGGGATCATCTTGAGGAGCCTATGGAAGTGGAGAAAACCACACCATGTTCTTTTACTCCACATTGTCCTCAGTAACTAGGAAACAGACCTATCTGGTACATACTTCAGCTGATAGTGGCCTAGACTTGCTCTTTCAAAGATAGGAAGGGCACTTCAGAGGCTTGGGGAAGGGATAAGTTTATCACCCAACACATTCTGCTACAGGATTTTAAACCAAAACTACACAAATCCATCCAATAGAGACTTGGCTTTAAGTAAATATACCCTCTGTGTCAGGCCACATGTGGAGCGTAAGACTTGTTTGAGGGAAGAGGTTTGCTGTGTCTCTCCGTTCTCCTCTCCACAGATATGTGTTTCCTGAAAAGTATATTCCATGTACATCGGCCTCATTTCCGGCGCTGAATAAGTACCACACGACCGAATCTCCTTTGCACATAGTGAGACCCGGCTGATTCCCATACATGAATCCATTCATGGCTGTAAAAGTTGGGAAATAACATTTTGGAAGTGGTTTAGATTCTACTACATGACAACCTCACAGACTTTCCAGGACCAACTTTGTTTTTTTAATTTTTAAAAGACCTATTCAGGCTTGCCCACGCTTTATGTGTCAGGAGTATCCTTGCAACTCCTTGTGGTTCCTGGCATTTCAGAGCAGCCGCTGGCTGAAAGGAGCAGAGCTGAATGCATAGTTCTTGTTCTATGCTAGTGTCCCTAGCAACCTGGGAATCCCACTGCTCTTCCTGGCTAAAACAATGATTCTGTTAT-A

Variant names:

• chr3-149186167-ATGAAAAGTTTAGGTGCAGAATATTTATGGGAGTCATTCCCCTTCTAGTCTGATTTTCCAGCTATCTTTAAAAGGACCATAATCTAAAAAGGGATCATCTTGAGGAGCCTATGGAAGTGGAGAAAACCACACCATGTTCTTTTACTCCACATTGTCCTCAGTAACTAGGAAACAGACCTATCTGGTACATACTTCAGCTGATAGTGGCCTAGACTTGCTCTTTCAAAGATAGGAAGGGCACTTCAGAGGCTTGGGGAAGGGATAAGTTTATCACCCAACACATTCTGCTACAGGATTTTAAACCAAAACTACACAAATCCATCCAATAGAGACTTGGCTTTAAGTAAATATACCCTCTGTGTCAGGCCACATGTGGAGCGTAAGACTTGTTTGAGGGAAGAGGTTTGCTGTGTCTCTCCGTTCTCCTCTCCACAGATATGTGTTTCCTGAAAAGTATATTCCATGTACATCGGCCTCATTTCCGGCGCTGAATAAGTACCACACGACCGAATCTCCTTTGCACATAGTGAGACCCGGCTGATTCCCATACATGAATCCATTCATGGCTGTAAAAGTTGGGAAATAACATTTTGGAAGTGGTTTAGATTCTACTACATGACAACCTCACAGACTTTCCAGGACCAACTTTGTTTTTTTAATTTTTAAAAGACCTATTCAGGCTTGCCCACGCTTTATGTGTCAGGAGTATCCTTGCAACTCCTTGTGGTTCCTGGCATTTCAGAGCAGCCGCTGGCTGAAAGGAGCAGAGCTGAATGCATAGTTCTTGTTCTATGCTAGTGTCCCTAGCAACCTGGGAATCCCACTGCTCTTCCTGGCTAAAACAATGATTCTGTTAT-A
• rs1553759338
• NM_000096.4:c.1865-291_2077+352del

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

The NM_000096.4(CP):​c.1865-291_2077+352del variant causes a exon loss, splice acceptor, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CP NM_000096.4 exon_loss, splice_acceptor, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.39
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06660413 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 3-149186167-ATGAAAAGTTTAGGTGCAGAATATTTATGGGAGTCATTCCCCTTCTAGTCTGATTTTCCAGCTATCTTTAAAAGGACCATAATCTAAAAAGGGATCATCTTGAGGAGCCTATGGAAGTGGAGAAAACCACACCATGTTCTTTTACTCCACATTGTCCTCAGTAACTAGGAAACAGACCTATCTGGTACATACTTCAGCTGATAGTGGCCTAGACTTGCTCTTTCAAAGATAGGAAGGGCACTTCAGAGGCTTGGGGAAGGGATAAGTTTATCACCCAACACATTCTGCTACAGGATTTTAAACCAAAACTACACAAATCCATCCAATAGAGACTTGGCTTTAAGTAAATATACCCTCTGTGTCAGGCCACATGTGGAGCGTAAGACTTGTTTGAGGGAAGAGGTTTGCTGTGTCTCTCCGTTCTCCTCTCCACAGATATGTGTTTCCTGAAAAGTATATTCCATGTACATCGGCCTCATTTCCGGCGCTGAATAAGTACCACACGACCGAATCTCCTTTGCACATAGTGAGACCCGGCTGATTCCCATACATGAATCCATTCATGGCTGTAAAAGTTGGGAAATAACATTTTGGAAGTGGTTTAGATTCTACTACATGACAACCTCACAGACTTTCCAGGACCAACTTTGTTTTTTTAATTTTTAAAAGACCTATTCAGGCTTGCCCACGCTTTATGTGTCAGGAGTATCCTTGCAACTCCTTGTGGTTCCTGGCATTTCAGAGCAGCCGCTGGCTGAAAGGAGCAGAGCTGAATGCATAGTTCTTGTTCTATGCTAGTGTCCCTAGCAACCTGGGAATCCCACTGCTCTTCCTGGCTAAAACAATGATTCTGTTAT-A is Pathogenic according to our data. Variant chr3-149186167-ATGAAAAGTTTAGGTGCAGAATATTTATGGGAGTCATTCCCCTTCTAGTCTGATTTTCCAGCTATCTTTAAAAGGACCATAATCTAAAAAGGGATCATCTTGAGGAGCCTATGGAAGTGGAGAAAACCACACCATGTTCTTTTACTCCACATTGTCCTCAGTAACTAGGAAACAGACCTATCTGGTACATACTTCAGCTGATAGTGGCCTAGACTTGCTCTTTCAAAGATAGGAAGGGCACTTCAGAGGCTTGGGGAAGGGATAAGTTTATCACCCAACACATTCTGCTACAGGATTTTAAACCAAAACTACACAAATCCATCCAATAGAGACTTGGCTTTAAGTAAATATACCCTCTGTGTCAGGCCACATGTGGAGCGTAAGACTTGTTTGAGGGAAGAGGTTTGCTGTGTCTCTCCGTTCTCCTCTCCACAGATATGTGTTTCCTGAAAAGTATATTCCATGTACATCGGCCTCATTTCCGGCGCTGAATAAGTACCACACGACCGAATCTCCTTTGCACATAGTGAGACCCGGCTGATTCCCATACATGAATCCATTCATGGCTGTAAAAGTTGGGAAATAACATTTTGGAAGTGGTTTAGATTCTACTACATGACAACCTCACAGACTTTCCAGGACCAACTTTGTTTTTTTAATTTTTAAAAGACCTATTCAGGCTTGCCCACGCTTTATGTGTCAGGAGTATCCTTGCAACTCCTTGTGGTTCCTGGCATTTCAGAGCAGCCGCTGGCTGAAAGGAGCAGAGCTGAATGCATAGTTCTTGTTCTATGCTAGTGTCCCTAGCAACCTGGGAATCCCACTGCTCTTCCTGGCTAAAACAATGATTCTGTTAT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 488148.Status of the report is no_assertion_criteria_provided, 0 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.1865-291_2077+352del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 11 of 19	NP_000087.2
	CP	NR_046371.2		n.1901+1029_1902-722del		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.1865-291_2077+352del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 11 of 19	ENSP00000264613.6
	CP	ENST00000494544.1	TSL:1	c.1214-291_1426+352del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 8 of 16	ENSP00000420545.1
	CP	ENST00000489736.5	TSL:1	n.1090-291_1654del		splice_acceptor splice_region intron non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Deficiency of ferroxidase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

Splicing

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

Other links and lift over

dbSNP: rs1553759338; hg19: chr3-148903954;