rs35331711

Positions:

chr3-149199783-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000096.4(CP):c.1430C>T(p.Pro477Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,614,060 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 16 hom. )

Consequence

CP
NM_000096.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 8.30

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041800678).

BP6

Variant 3-149199783-G-A is Benign according to our data. Variant chr3-149199783-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210755.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr3-149199783-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 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.1430C>T	p.Pro477Leu	missense_variant	8/19	ENST00000264613.11	NP_000087.2	P00450A5PL27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11 linkuse as main transcript	c.1430C>T	p.Pro477Leu	missense_variant	8/19	1	NM_000096.4	ENSP00000264613.6		P00450

Frequencies

GnomAD3 genomes

AF:

0.00230

AC:

350

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00413

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00235

AC:

590

AN:

251416

Hom.:

AF XY:

0.00247

AC XY:

336

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00328

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00399

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00373

AC:

5451

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00370

AC XY:

2691

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.00364

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00120

Gnomad4 NFE exome

AF:

0.00453

Gnomad4 OTH exome

AF:

0.00263

GnomAD4 genome

AF:

0.00230

AC:

350

AN:

152248

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00413

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00375

Hom.:

Bravo

AF:

0.00222

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00253

AC:

307

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00398

EpiControl

AF:

0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of ferroxidase

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
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. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2023	Variant summary: CP c.1430C>T (p.Pro477Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 251416 control chromosomes, predominantly at a frequency of 0.004 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in CP causing Neurodegeneration With Brain Iron Accumulation phenotype (0.00019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1430C>T has been reported in the literature in individuals affected with Hyperferritinemia (Corradini_2021). This report does not provide unequivocal conclusions about association of the variant with Neurodegeneration With Brain Iron Accumulation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33774058). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=4) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CP p.Pro477Leu variant was identified in 1 of 352 proband chromosomes (frequency: 0.003) from individuals or families with Parkinson disease but was also present in 1 of 360 control chromosomes (frequency: 0.003) from healthy individuals (Hochstrasser_2004_PMID:15557511). The variant was identified in dbSNP (ID: rs35331711), LOVD 3.0 and ClinVar (classified as uncertain significance by Illumina and Genetic Services Laboratory, University of Chicago, as likely benign by Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen and as benign by Invitae). The variant was identified in control databases in 680 of 282808 chromosomes (2 homozygous) at a frequency of 0.002404 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 521 of 129134 chromosomes (freq: 0.004035), Ashkenazi Jewish in 35 of 10364 chromosomes (freq: 0.003377), Other in 20 of 7222 chromosomes (freq: 0.002769), Latino in 50 of 35438 chromosomes (freq: 0.001411), European (Finnish) in 34 of 25124 chromosomes (freq: 0.001353), African in 19 of 24964 chromosomes (freq: 0.000761) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the East Asian population. Although the p.Pro477 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CP: BS2 -

CP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 17, 2022

This variant is classified as likely 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

Uncertain

0.49

BayesDel_addAF

Benign

0.010

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

.;T

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.042

T;T

MetaSVM

Pathogenic

0.94

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Vest4

0.70

MVP

0.98

MPC

0.50

ClinPred

0.072

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.92

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