rs16861582

Positions:

• chr3-149178643-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000096.4(CP):​c.2662-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,573,888 control chromosomes in the GnomAD database, including 70,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8898 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61361 hom.)
• Consequence: CP NM_000096.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001142
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.693

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-149178643-A-G is Benign according to our data. Variant chr3-149178643-A-G is described in ClinVar as [Benign]. Clinvar id is 194589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-149178643-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CP	NM_000096.4	c.2662-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000264613.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CP	ENST00000264613.11	c.2662-12T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000096.4	P1

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50126 AN: 151884 Hom.: 8889 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.286

GnomAD3 exomes AF: 0.295 AC: 71017 AN: 241012 Hom.: 11028 AF XY: 0.294 AC XY: 38340 AN XY: 130572

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.368

Gnomad SAS exome AF: 0.291

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.291 AC: 413383 AN: 1421886 Hom.: 61361 Cov.: 26 AF XY: 0.290 AC XY: 205778 AN XY: 709336

Gnomad4 AFR exome AF: 0.449

Gnomad4 AMR exome AF: 0.213

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.360

Gnomad4 SAS exome AF: 0.289

Gnomad4 FIN exome AF: 0.363

Gnomad4 NFE exome AF: 0.287

Gnomad4 OTH exome AF: 0.287

GnomAD4 genome AF: 0.330 AC: 50180 AN: 152002 Hom.: 8898 Cov.: 32 AF XY: 0.332 AC XY: 24671 AN XY: 74300

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.367

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.286

Gnomad4 OTH AF: 0.284

Alfa AF: 0.291 Hom.: 5032

Bravo AF: 0.327

Asia WGS AF: 0.335 AC: 1164 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Deficiency of ferroxidase Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.020		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: rs16861582; hg19: chr3-148896430;