NM_000096.4:c.548T>G

Variant names:

• chr3-149210226-A-C
• rs386134123
• NM_000096.4:c.548T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.86
• Publications: 1 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CP	NM_000096.4	c.548T>G	p.Ile183Ser	missense_variant	Exon 3 of 19	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11	c.548T>G	p.Ile183Ser	missense_variant	Exon 3 of 19	1	NM_000096.4	ENSP00000264613.6
CP	ENST00000490639.5	n.580T>G		non_coding_transcript_exon_variant	Exon 3 of 17	1
CP	ENST00000481169.5	n.548T>G		non_coding_transcript_exon_variant	Exon 3 of 18	2		ENSP00000418773.1
CP	ENST00000455472.3	c.*132T>G		downstream_gene_variant		5		ENSP00000426888.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251376 AF XY: 0.00000736

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.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		6.9
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.012	D
Sift4G	Benign	0.10	T
Vest4		0.79
MutPred		0.74		Gain of disorder (P = 0.0086);
MVP		0.98
MPC		0.57
ClinPred		0.90	D
GERP RS		5.8
gMVP		0.88
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs386134123; hg19: chr3-148928013;