rs151304828

Positions:

• chr3-149179646-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000096.4(CP):​c.2571C>T​(p.Tyr857=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,603,502 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (10 hom.)
• Consequence: CP NM_000096.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.0140

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-149179646-G-A is Benign according to our data. Variant chr3-149179646-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210756.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}. Variant chr3-149179646-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.014 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CP	NM_000096.4	c.2571C>T	p.Tyr857=	synonymous_variant	15/19	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11	c.2571C>T	p.Tyr857=	synonymous_variant	15/19	1	NM_000096.4	ENSP00000264613	P1

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 279 AN: 151336 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000778

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000481

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00162 AC: 406 AN: 250592 Hom.: 0 AF XY: 0.00157 AC XY: 212 AN XY: 135446

Gnomad AFR exome AF: 0.000986

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.00288

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00299 AC: 4346 AN: 1452044 Hom.: 10 Cov.: 31 AF XY: 0.00285 AC XY: 2058 AN XY: 722398

Gnomad4 AFR exome AF: 0.000662

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.000621

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.000439

Gnomad4 NFE exome AF: 0.00366

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00184 AC: 279 AN: 151458 Hom.: 1 Cov.: 32 AF XY: 0.00147 AC XY: 109 AN XY: 73974

Gnomad4 AFR AF: 0.000775

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000481

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00260 Hom.: 0

Bravo AF: 0.00197

EpiCase AF: 0.00289

EpiControl AF: 0.00285

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CP: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2020	- -

Deficiency of ferroxidase Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 27, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.3
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs151304828; hg19: chr3-148897433;