rs200683433

Positions:

• chr3-149212616-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP3_Moderate BP6

The NM_000096.4(CP):​c.229G>C​(p.Asp77His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: CP NM_000096.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:1
• Conservation: PhyloP100: 1.10

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• BP6: Variant 3-149212616-C-G is Benign according to our data. Variant chr3-149212616-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42050.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CP	NM_000096.4	c.229G>C	p.Asp77His	missense_variant	2/19	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11	c.229G>C	p.Asp77His	missense_variant	2/19	1	NM_000096.4	ENSP00000264613.6
CP	ENST00000490639.5	n.261G>C		non_coding_transcript_exon_variant	2/17	1
CP	ENST00000455472.3	c.349G>C	p.Asp117His	missense_variant	3/4	5		ENSP00000426888.1
CP	ENST00000481169.5	n.229G>C		non_coding_transcript_exon_variant	2/18	2		ENSP00000418773.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251164 Hom.: 0 AF XY: 0.000192 AC XY: 26 AN XY: 135748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000684 AC: 100 AN: 1461740 Hom.: 0 Cov.: 32 AF XY: 0.0000976 AC XY: 71 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000672

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000637 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of ferroxidase Pathogenic:1 Uncertain:1 Benign:1

Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 18, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 08, 2023

Variant summary: CP c.229G>C (p.Asp77His) 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 0.00014 in 251164 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CP causing Neurodegeneration With Brain Iron Accumulation (0.00014 vs 0.00019), allowing no conclusion about variant significance. c.229G>C has been reported in the literature as a presumably compound heterozygous genotype and as a non-informative genotype (second allele not specified) in at-least two individuals affected with Iron overload/Aceruloplasminemia (example, PMID: 17710675, cited in 32235485). These data do not allow any conclusion about variant significance. To our knowledge, no direct experimental evidence demonstrating an impact on protein function has been reported. Although one study characterized the variant as functionally incompetent by testing its ability to prevent ferroportin degradation in rat glioma C6 cells silenced for endogenous ceruloplasmin (example, PMID: 19095659). But the data as presented is not quantifiable into residual activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;.
Vest4		0.87
MVP		0.96
MPC		0.52
ClinPred		0.82	D
GERP RS		4.5
gMVP		0.95

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: rs200683433; hg19: chr3-148930403;