dbSNP rs386134123: CP:p.Ile183Ser (chr3-149210226-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000096.4(CP):c.548T>G(p.Ile183Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I183T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CP
NM_000096.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.86

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.907

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000096.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	NM_000096.4	MANE Select	c.548T>G	p.Ile183Ser	missense	Exon 3 of 19	NP_000087.2
	CP	NR_046371.2		n.585T>G		non_coding_transcript_exon	Exon 3 of 18

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CP	ENST00000264613.11	TSL:1 MANE Select	c.548T>G	p.Ile183Ser	missense	Exon 3 of 19	ENSP00000264613.6
CP	ENST00000490639.5	TSL:1	n.580T>G		non_coding_transcript_exon	Exon 3 of 17
CP	ENST00000481169.5	TSL:2	n.548T>G		non_coding_transcript_exon	Exon 3 of 18	ENSP00000418773.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251376

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.1

PhyloP100

6.9

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.74

Sift

Uncertain

0.012

Sift4G

Benign

0.10

Vest4

0.79

MutPred

0.74

Gain of disorder (P = 0.0086)

MVP

0.98

MPC

0.57

ClinPred

0.90

GERP RS

5.8

gMVP

0.88

Mutation Taster

=59/41

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over