rs386134122

Variant names:

• chr3-149210281-G-C
• rs386134122
• NM_000096.4:c.493C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-149210281-G-C
• chr3-149210281-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000096.4(CP):​c.493C>G​(p.Gln165Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CP NM_000096.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.14
• Publications: 2 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-149210281-G-C is Pathogenic according to our data. Variant chr3-149210281-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 42120.Status of the report is no_assertion_criteria_provided, 0 stars.

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.493C>G	p.Gln165Glu	missense	Exon 3 of 19	NP_000087.2
	CP	NR_046371.2		n.530C>G		non_coding_transcript_exon	Exon 3 of 18

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.493C>G	p.Gln165Glu	missense	Exon 3 of 19	ENSP00000264613.6
	CP	ENST00000490639.5	TSL:1	n.525C>G		non_coding_transcript_exon	Exon 3 of 17
	CP	ENST00000481169.5	TSL:2	n.493C>G		non_coding_transcript_exon	Exon 3 of 18	ENSP00000418773.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Deficiency of ferroxidase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.57	D
PhyloP100		5.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.56
Sift	Benign	0.44	T
Sift4G	Benign	0.18	T
Vest4		0.73
MutPred		0.54		Loss of glycosylation at P167 (P = 0.0509)
MVP		0.92
MPC		0.12
ClinPred		0.75	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.82
Mutation Taster		=33/67	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386134122; hg19: chr3-148928068;