3-149177867-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000096.4(CP):c.2991T>C(p.His997His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0416 in 1,613,350 control chromosomes in the GnomAD database, including 1,660 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 98 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1562 hom. )

Consequence

CP
NM_000096.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.990

Publications

10 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 3-149177867-A-G is Benign according to our data. Variant chr3-149177867-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.99 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0304 (4625/152276) while in subpopulation NFE AF = 0.0441 (2997/68022). AF 95% confidence interval is 0.0427. There are 98 homozygotes in GnomAd4. There are 2290 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 98 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CP	NM_000096.4 link	c.2991T>C	p.His997His	synonymous_variant	Exon 17 of 19	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11 link	c.2991T>C	p.His997His	synonymous_variant	Exon 17 of 19	1	NM_000096.4	ENSP00000264613.6

Frequencies

GnomAD3 genomes

AF:

0.0304

AC:

4628

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00965

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0201

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0305

Gnomad FIN

AF:

0.0613

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0441

Gnomad OTH

AF:

0.0292

GnomAD2 exomes

AF:

0.0334

AC:

8405

AN:

251326

AF XY:

0.0354

show subpopulations

Gnomad AFR exome

AF:

0.00763

Gnomad AMR exome

AF:

0.0156

Gnomad ASJ exome

AF:

0.0146

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0645

Gnomad NFE exome

AF:

0.0434

Gnomad OTH exome

AF:

0.0377

GnomAD4 exome

AF:

0.0428

AC:

62464

AN:

1461074

Hom.:

1562

Cov.:

AF XY:

0.0426

AC XY:

30940

AN XY:

726854

show subpopulations

African (AFR)

AF:

0.00828

AC:

277

AN:

33462

American (AMR)

AF:

0.0160

AC:

715

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

348

AN:

26126

East Asian (EAS)

AF:

0.000101

AC:

AN:

39684

South Asian (SAS)

AF:

0.0349

AC:

3008

AN:

86246

European-Finnish (FIN)

AF:

0.0628

AC:

3356

AN:

53412

Middle Eastern (MID)

AF:

0.0522

AC:

301

AN:

5768

European-Non Finnish (NFE)

AF:

0.0471

AC:

52357

AN:

1111288

Other (OTH)

AF:

0.0348

AC:

2098

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

2849

5697

8546

11394

14243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1956

3912

5868

7824

9780

<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:

0.0304

AC:

4625

AN:

152276

Hom.:

Cov.:

AF XY:

0.0308

AC XY:

2290

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00965

AC:

401

AN:

41570

American (AMR)

AF:

0.0201

AC:

307

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0303

AC:

146

AN:

4822

European-Finnish (FIN)

AF:

0.0613

AC:

651

AN:

10612

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0441

AC:

2997

AN:

68022

Other (OTH)

AF:

0.0274

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

230

459

689

918

1148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0376

Hom.:

Bravo

AF:

0.0267

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0412

EpiControl

AF:

0.0431

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 06, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deficiency of ferroxidase

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hermansky-Pudlak syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.1

(source)

DANN

Benign

0.74

PhyloP100

0.99

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over