rs701753

chr3-149198448-T-Achr3-149198448-T-Cchr3-149198448-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/18 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0930

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 198992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-149198448-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CP	NM_000096.4	c.1632A>T	p.Glu544Asp	missense_variant	9/19	ENST00000264613.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CP	ENST00000264613.11	c.1632A>T	p.Glu544Asp	missense_variant	9/19	1	NM_000096.4	P1

Frequencies

GnomAD3 genomes AF: 0.873 AC: 132690 AN: 152002 Hom.: 58797 Cov.: 31

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

GnomAD3 exomes AF: 0.923 AC: 231447 AN: 250842 Hom.: 107415 AF XY: 0.922 AC XY: 125080 AN XY: 135666

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 SAS exome AF: 0.875

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.: 36 AF XY: 0.929 AC XY: 673906 AN XY: 725250

Gnomad4 AFR exome AF: 0.685

Gnomad4 AMR exome AF: 0.953

Gnomad4 ASJ exome AF: 0.938

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.873

Gnomad4 FIN exome AF: 0.943

Gnomad4 NFE exome AF: 0.939

Gnomad4 OTH exome AF: 0.924

GnomAD4 genome AF: 0.873 AC: 132774 AN: 152120 Hom.: 58829 Cov.: 31 AF XY: 0.873 AC XY: 64906 AN XY: 74348

Gnomad4 AFR AF: 0.698

Gnomad4 AMR AF: 0.940

Gnomad4 ASJ AF: 0.935

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.876

Gnomad4 FIN AF: 0.942

Gnomad4 NFE AF: 0.938

Gnomad4 OTH AF: 0.900

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

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

Deficiency of ferroxidase Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	5.6
Dann	Benign	0.44
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.12	N
MetaRNN	Benign	0.0000011	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.9	N;N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.022
MutPred		0.49		Gain of ubiquitination at K547 (P = 0.0632);.;
MPC		0.085
ClinPred		0.0051	T
GERP RS		-2.5
gMVP		0.67

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

Other links and lift over

dbSNP: rs701753; hg19: chr3-148916235;