rs1053709

chr3-149186647-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000096.4(CP):c.1950A>C(p.Gly650=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0556 in 1,614,152 control chromosomes in the GnomAD database, including 2,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (191 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2641 hom.)
• Consequence: CP NM_000096.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.733

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 3-149186647-T-G is Benign according to our data. Variant chr3-149186647-T-G is described in ClinVar as [Benign]. Clinvar id is 128838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-149186647-T-G is described in Lovd as [Benign]. Variant chr3-149186647-T-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.733 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CP	NM_000096.4	c.1950A>C	p.Gly650=	synonymous_variant	11/19	ENST00000264613.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CP	ENST00000264613.11	c.1950A>C	p.Gly650=	synonymous_variant	11/19	1	NM_000096.4	P1

Frequencies

GnomAD3 genomes AF: 0.0417 AC: 6344 AN: 152186 Hom.: 191 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0270

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0657

Gnomad OTH AF: 0.0546

GnomAD3 exomes AF: 0.0441 AC: 11080 AN: 251428 Hom.: 344 AF XY: 0.0453 AC XY: 6161 AN XY: 135882

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0680

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0330

Gnomad FIN exome AF: 0.0295

Gnomad NFE exome AF: 0.0639

Gnomad OTH exome AF: 0.0575

GnomAD4 exome AF: 0.0571 AC: 83456 AN: 1461848 Hom.: 2641 Cov.: 31 AF XY: 0.0564 AC XY: 41030 AN XY: 727234

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.0297

Gnomad4 ASJ exome AF: 0.0703

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0335

Gnomad4 FIN exome AF: 0.0322

Gnomad4 NFE exome AF: 0.0643

Gnomad4 OTH exome AF: 0.0568

GnomAD4 genome AF: 0.0417 AC: 6346 AN: 152304 Hom.: 191 Cov.: 32 AF XY: 0.0401 AC XY: 2983 AN XY: 74476

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.0396

Gnomad4 ASJ AF: 0.0620

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0255

Gnomad4 FIN AF: 0.0270

Gnomad4 NFE AF: 0.0657

Gnomad4 OTH AF: 0.0541

Alfa AF: 0.0560 Hom.: 137

Bravo AF: 0.0413

Asia WGS AF: 0.0190 AC: 70 AN: 3478

EpiCase AF: 0.0638

EpiControl AF: 0.0671

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	-	- -

Deficiency of ferroxidase Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	8.4
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1053709; hg19: chr3-148904434;