rs386134127

Variant names:

• chr3-149206327-G-T
• rs386134127
• NM_000096.4:c.1049C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000096.4(CP):​c.1049C>A​(p.Ala350Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,642 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CP NM_000096.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.50

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 3-149206327-G-T is Pathogenic according to our data. Variant chr3-149206327-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42047.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CP	NM_000096.4	c.1049C>A	p.Ala350Asp	missense_variant	Exon 6 of 19	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11	c.1049C>A	p.Ala350Asp	missense_variant	Exon 6 of 19	1	NM_000096.4	ENSP00000264613.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461642 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodegeneration with brain iron accumulation Pathogenic:1

Dec 18, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CP c.1049C>A (p.Ala350Asp) results in a non-conservative amino acid change located in the Multicopper oxidase domain (IPR001117) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251124 control chromosomes (gnomAD). c.1049C>A (aka. A331D) has been reported in the homozygous state in the literature in multiple individuals affected with clinical or laboratory features of Neurodegeneration With Brain Iron Accumulation (examples, Perez-Aguilar_2005, Kassubek_2017), including at least 1 family where this variant segregated with near complete absence of detectable ceruloplasmin in serum. These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function and demonstrated that the variant protein was retained in the endoplasmic reticulum, presumably due to misfolding (Kono_2010), furthermore indirect evidence indicated a partial ferroxidase activity (di Patti_2009). The following publications have been ascertained in the context of this evaluation (PMID: 28431603, 20655381, 15885371, 32235485, 19095659). ClinVar contains an entry for this variant (Variation ID: 42047). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Deficiency of ferroxidase Pathogenic:1

Apr 18, 2013

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	.;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.99	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.94
MutPred		0.91		Loss of sheet (P = 0.0817);.;
MVP		0.99
MPC		0.61
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.98

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: rs386134127; hg19: chr3-148924114;