rs701753

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000096.4(CP):c.1632A>T(p.Glu544Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.925 in 1,609,336 control chromosomes in the GnomAD database, including 691,101 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.87 ( 58829 hom., cov: 31)

Exomes 𝑓: 0.93 ( 632272 hom. )

Consequence

CP
NM_000096.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0930

Publications

42 publications found

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 Gene-Disease associations (from GenCC):

aceruloplasminemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
disorder of iron metabolism and transport
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0621669E-6).

BP6

Variant 3-149198448-T-A is Benign according to our data. Variant chr3-149198448-T-A is described in ClinVar as Benign. ClinVar VariationId is 198992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000096.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	NM_000096.4	MANE Select	c.1632A>T	p.Glu544Asp	missense	Exon 9 of 19	NP_000087.2
	CP	NR_046371.2		n.1669A>T		non_coding_transcript_exon	Exon 9 of 18

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CP	ENST00000264613.11	TSL:1 MANE Select	c.1632A>T	p.Glu544Asp	missense	Exon 9 of 19	ENSP00000264613.6
CP	ENST00000494544.1	TSL:1	c.981A>T	p.Glu327Asp	missense	Exon 6 of 16	ENSP00000420545.1
CP	ENST00000489736.5	TSL:1	n.857A>T		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes

AF:

0.873

AC:

132690

AN:

152002

Hom.:

58797

Cov.:

show subpopulations

Gnomad AFR

AF:

0.698

Gnomad AMI

AF:

0.941

Gnomad AMR

AF:

0.940

Gnomad ASJ

AF:

0.935

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.877

Gnomad FIN

AF:

0.942

Gnomad MID

AF:

0.889

Gnomad NFE

AF:

0.939

Gnomad OTH

AF:

0.898

GnomAD2 exomes

AF:

0.923

AC:

231447

AN:

250842

AF XY:

0.922

show subpopulations

Gnomad AFR exome

AF:

0.688

Gnomad AMR exome

AF:

0.956

Gnomad ASJ exome

AF:

0.938

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.941

Gnomad NFE exome

AF:

0.941

Gnomad OTH exome

AF:

0.928

GnomAD4 exome

AF:

0.930

AC:

1355729

AN:

1457216

Hom.:

632272

Cov.:

AF XY:

0.929

AC XY:

673906

AN XY:

725250

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.685

AC:

22764

AN:

33240

American (AMR)

AF:

0.953

AC:

42596

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.938

AC:

24483

AN:

26106

East Asian (EAS)

AF:

1.00

AC:

39684

AN:

39692

South Asian (SAS)

AF:

0.873

AC:

75176

AN:

86112

European-Finnish (FIN)

AF:

0.943

AC:

50336

AN:

53406

Middle Eastern (MID)

AF:

0.888

AC:

5098

AN:

5744

European-Non Finnish (NFE)

AF:

0.939

AC:

1039932

AN:

1107952

Other (OTH)

AF:

0.924

AC:

55660

AN:

60250

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.398

Heterozygous variant carriers

4089

8178

12267

16356

20445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21444

42888

64332

85776

107220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.873

AC:

132774

AN:

152120

Hom.:

58829

Cov.:

AF XY:

0.873

AC XY:

64906

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.698

AC:

28926

AN:

41432

American (AMR)

AF:

0.940

AC:

14373

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.935

AC:

3243

AN:

3470

East Asian (EAS)

AF:

0.999

AC:

5168

AN:

5172

South Asian (SAS)

AF:

0.876

AC:

4217

AN:

4812

European-Finnish (FIN)

AF:

0.942

AC:

9984

AN:

10594

Middle Eastern (MID)

AF:

0.888

AC:

261

AN:

294

European-Non Finnish (NFE)

AF:

0.938

AC:

63842

AN:

68026

Other (OTH)

AF:

0.900

AC:

1902

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

780

1561

2341

3122

3902

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

890

1780

2670

3560

4450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.906

Hom.:

11546

Bravo

AF:

0.866

ESP6500AA

AF:

0.699

AC:

3080

ESP6500EA

AF:

0.936

AC:

8024

ExAC

AF:

0.916

AC:

111255

EpiCase

AF:

0.933

EpiControl

AF:

0.932

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Deficiency of ferroxidase (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.30

CADD

Benign

5.6

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.0070

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0000011

MetaSVM

Benign

-0.94

PhyloP100

0.093

PrimateAI

Benign

0.41

PROVEAN

Benign

2.9

REVEL

Uncertain

0.30

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.022

MutPred

0.49

Gain of ubiquitination at K547 (P = 0.0632)

MPC

0.085

ClinPred

0.0051

GERP RS

-2.5

gMVP

0.67

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over