rs34394958

Variant names:

• chr3-149177867-A-C
• rs34394958
• NM_000096.4:c.2991T>G

Your query was ambiguous. Multiple possible variants found:

• chr3-149177867-A-C
• chr3-149177867-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000096.4(CP):​c.2991T>G​(p.His997Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H997Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CP NM_000096.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.990
• Publications: 10 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity CERU_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CP	NM_000096.4	c.2991T>G	p.His997Gln	missense_variant	Exon 17 of 19	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11	c.2991T>G	p.His997Gln	missense_variant	Exon 17 of 19	1	NM_000096.4	ENSP00000264613.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Deficiency of ferroxidase Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T;.;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.76	D
PhyloP100		0.99
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.8	D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Vest4		0.98
MutPred		0.94		.;Loss of sheet (P = 0.0817);.;
MVP		0.96
MPC		0.50
ClinPred		1.0	D
GERP RS		-0.92
gMVP		0.94
Mutation Taster		=5/95	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: rs34394958; hg19: chr3-148895654;