rs56033670

Positions:

chr3-149182037-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000096.4(CP):c.2522C>G(p.Thr841Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00504 in 1,588,296 control chromosomes in the GnomAD database, including 36 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 0.0044 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0051 ( 36 hom. )

Consequence

CP
NM_000096.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 5.91

Variant links:

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 links:

CP (HGNC:):

CP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005704552).

BP6

Variant 3-149182037-G-C is Benign according to our data. Variant chr3-149182037-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 284863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-149182037-G-C is described in Lovd as [Likely_benign]. Variant chr3-149182037-G-C is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CP	NM_000096.4 linkuse as main transcript	c.2522C>G	p.Thr841Arg	missense_variant	14/19	ENST00000264613.11	NP_000087.2	P00450A5PL27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CP	ENST00000264613.11 linkuse as main transcript	c.2522C>G	p.Thr841Arg	missense_variant	14/19	1	NM_000096.4	ENSP00000264613.6	P00450
CP	ENST00000494544.1 linkuse as main transcript	c.1871C>G	p.Thr624Arg	missense_variant	11/16	1		ENSP00000420545.1	H7C5R1
CP	ENST00000490639.5 linkuse as main transcript	n.2554C>G		non_coding_transcript_exon_variant	14/17	1
CP	ENST00000481169.5 linkuse as main transcript	n.2309C>G		non_coding_transcript_exon_variant	13/18	2		ENSP00000418773.1	E9PFZ2

Frequencies

GnomAD3 genomes

AF:

0.00440

AC:

616

AN:

139914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00405

Gnomad ASJ

AF:

0.0256

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000444

Gnomad FIN

AF:

0.000492

Gnomad MID

AF:

0.0155

Gnomad NFE

AF:

0.00609

Gnomad OTH

AF:

0.00943

GnomAD3 exomes

AF:

0.00428

AC:

1076

AN:

251424

Hom.:

AF XY:

0.00417

AC XY:

566

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00278

Gnomad ASJ exome

AF:

0.0258

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00544

Gnomad OTH exome

AF:

0.00782

GnomAD4 exome

AF:

0.00510

AC:

7389

AN:

1448308

Hom.:

Cov.:

AF XY:

0.00506

AC XY:

3645

AN XY:

720516

show subpopulations

Gnomad4 AFR exome

AF:

0.00109

Gnomad4 AMR exome

AF:

0.00292

Gnomad4 ASJ exome

AF:

0.0254

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.000593

Gnomad4 FIN exome

AF:

0.000587

Gnomad4 NFE exome

AF:

0.00548

Gnomad4 OTH exome

AF:

0.00654

GnomAD4 genome

AF:

0.00440

AC:

616

AN:

139988

Hom.:

Cov.:

AF XY:

0.00401

AC XY:

268

AN XY:

66866

show subpopulations

Gnomad4 AFR

AF:

0.00117

Gnomad4 AMR

AF:

0.00404

Gnomad4 ASJ

AF:

0.0256

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000445

Gnomad4 FIN

AF:

0.000492

Gnomad4 NFE

AF:

0.00609

Gnomad4 OTH

AF:

0.00937

Alfa

AF:

0.00658

Hom.:

Bravo

AF:

0.00410

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00381

AC:

463

EpiCase

AF:

0.00731

EpiControl

AF:

0.00676

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CP: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 28, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 21, 2019	- -

Deficiency of ferroxidase

Benign:3

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 03, 2021	- -

CP-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.44

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.66

.;D

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.70

.;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.0057

T;T

MetaSVM

Pathogenic

0.91

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.59

Sift

Benign

0.38

T;T

Sift4G

Benign

0.27

T;T

Vest4

0.88

MVP

0.97

MPC

0.23

ClinPred

0.047

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over