chr3-149198428-G-A

Position:

• chr3-149198428-G-A

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.1652C>T​(p.Thr551Ile) variant causes a missense change. The variant allele was found at a frequency of 0.031 in 1,612,482 control chromosomes in the GnomAD database, including 978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (65 hom., cov: 32)
  • Exomes 𝑓: 0.032 (913 hom.)
• Consequence: CP NM_000096.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:12
• Conservation: PhyloP100: 6.57

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 (MetaRNN=0.01101324).
• BP6: Variant 3-149198428-G-A is Benign according to our data. Variant chr3-149198428-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 42125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-149198428-G-A is described in Lovd as [Benign]. Variant chr3-149198428-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CP	NM_000096.4	c.1652C>T	p.Thr551Ile	missense_variant	9/19	ENST00000264613.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CP	ENST00000264613.11	c.1652C>T	p.Thr551Ile	missense_variant	9/19	1	NM_000096.4	P1

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3460 AN: 152130 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.00655

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.0610

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0326

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0285 AC: 7148 AN: 251032 Hom.: 142 AF XY: 0.0311 AC XY: 4223 AN XY: 135704

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.0326

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0647

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0307

Gnomad OTH exome AF: 0.0304

GnomAD4 exome AF: 0.0319 AC: 46572 AN: 1460234 Hom.: 913 Cov.: 30 AF XY: 0.0330 AC XY: 23995 AN XY: 726518

Gnomad4 AFR exome AF: 0.00568

Gnomad4 AMR exome AF: 0.0170

Gnomad4 ASJ exome AF: 0.0300

Gnomad4 EAS exome AF: 0.00222

Gnomad4 SAS exome AF: 0.0646

Gnomad4 FIN exome AF: 0.0235

Gnomad4 NFE exome AF: 0.0322

Gnomad4 OTH exome AF: 0.0312

GnomAD4 genome AF: 0.0227 AC: 3456 AN: 152248 Hom.: 65 Cov.: 32 AF XY: 0.0227 AC XY: 1691 AN XY: 74452

Gnomad4 AFR AF: 0.00655

Gnomad4 AMR AF: 0.0191

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0606

Gnomad4 FIN AF: 0.0188

Gnomad4 NFE AF: 0.0326

Gnomad4 OTH AF: 0.0256

Alfa AF: 0.0254 Hom.: 15

Bravo AF: 0.0204

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.0301 AC: 259

ExAC AF: 0.0288 AC: 3498

Asia WGS AF: 0.0270 AC: 94 AN: 3478

EpiCase AF: 0.0316

EpiControl AF: 0.0305

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of ferroxidase Pathogenic:1 Benign:6

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. -
Likely benign, criteria provided, single submitter	clinical testing	GenePathDx, GenePath diagnostics	Feb 01, 2017	25 years old, suspected case of Aceruloplasminemia. Next generation DNA sequencing ofperipheral blood sample has revealed the presence of two homozygous variants in the CP gene. The c.1652C>T variant is being classified as a ‘Variant of Unknown Significance, likely benign’, while the c.1679G>T variant is being classified as a ‘Variant of Unknown Significance, likely pathogenic’ based on available evidence in the databases and in silico mutation prediction methods. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, flagged submission	curation	GeneReviews	Apr 18, 2013	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 16, 2015	- -
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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	.;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.57	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.090
MPC		0.47
ClinPred		0.027	T
GERP RS		5.5
gMVP		0.90

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: rs61733458; hg19: chr3-148916215;