rs115552500

Positions:

chr3-149183513-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000096.4(CP):c.2378G>A(p.Arg793His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00991 in 1,611,260 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict 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 0.012 ( 16 hom., cov: 31)

Exomes 𝑓: 0.0097 ( 88 hom. )

Consequence

CP
NM_000096.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.42

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006608665).

BP6

Variant 3-149183513-C-T is Benign according to our data. Variant chr3-149183513-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-149183513-C-T is described in Lovd as [Benign]. Variant chr3-149183513-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0118 (1796/151754) while in subpopulation AFR AF= 0.0194 (802/41354). AF 95% confidence interval is 0.0183. There are 16 homozygotes in gnomad4. There are 866 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CP	NM_000096.4 linkuse as main transcript	c.2378G>A	p.Arg793His	missense_variant	13/19	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CP	ENST00000264613.11 linkuse as main transcript	c.2378G>A	p.Arg793His	missense_variant	13/19	1	NM_000096.4	ENSP00000264613	P1
CP	ENST00000494544.1 linkuse as main transcript	c.1727G>A	p.Arg576His	missense_variant	10/16	1		ENSP00000420545
CP	ENST00000490639.5 linkuse as main transcript	n.2410G>A		non_coding_transcript_exon_variant	13/17	1
CP	ENST00000481169.5 linkuse as main transcript	c.2165G>A	p.Arg722His	missense_variant, NMD_transcript_variant	12/18	2		ENSP00000418773

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1794

AN:

151636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000768

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.00731

AC:

1838

AN:

251338

Hom.:

AF XY:

0.00710

AC XY:

965

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.00746

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00327

Gnomad FIN exome

AF:

0.000741

Gnomad NFE exome

AF:

0.00883

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.00971

AC:

14175

AN:

1459506

Hom.:

Cov.:

AF XY:

0.00953

AC XY:

6922

AN XY:

726084

show subpopulations

Gnomad4 AFR exome

AF:

0.0178

Gnomad4 AMR exome

AF:

0.00756

Gnomad4 ASJ exome

AF:

0.00574

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00312

Gnomad4 FIN exome

AF:

0.00152

Gnomad4 NFE exome

AF:

0.0109

Gnomad4 OTH exome

AF:

0.0103

GnomAD4 genome

AF:

0.0118

AC:

1796

AN:

151754

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

866

AN XY:

74108

show subpopulations

Gnomad4 AFR

AF:

0.0194

Gnomad4 AMR

AF:

0.0121

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00291

Gnomad4 FIN

AF:

0.000768

Gnomad4 NFE

AF:

0.0102

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.00984

Hom.:

Bravo

AF:

0.0124

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.0202

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.00708

AC:

860

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0108

EpiControl

AF:

0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 04, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Deficiency of ferroxidase

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 04, 2022	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2020	This variant is associated with the following publications: (PMID: 15557511, 25758665, 26000822, 16150804) -

CP-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2019

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

0.071

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.047

.;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.040

LIST_S2

Uncertain

0.89

.;D

MetaRNN

Benign

0.0066

T;T

MetaSVM

Uncertain

0.46

MutationTaster

Benign

1.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.12

T;T

Sift4G

Benign

0.12

T;T

Vest4

0.15

MVP

0.84

MPC

0.18

ClinPred

0.012

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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