NM_000096.4:c.2285+312A>G

Variant names:

• chr3-149184927-T-C
• rs701755
• NM_000096.4:c.2285+312A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000096.4(CP):​c.2285+312A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 152,228 control chromosomes in the GnomAD database, including 2,115 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2115 hom., cov: 32)
• Consequence: CP NM_000096.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0730
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	NM_000096.4	MANE Select	c.2285+312A>G		intron	N/A	NP_000087.2
	CP	NR_046371.2		n.2109+312A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.2285+312A>G		intron	N/A	ENSP00000264613.6
	CP	ENST00000494544.1	TSL:1	c.1634+312A>G		intron	N/A	ENSP00000420545.1
	CP	ENST00000490639.5	TSL:1	n.2317+312A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24433 AN: 152110 Hom.: 2112 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.163

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.161 AC: 24452 AN: 152228 Hom.: 2115 Cov.: 32 AF XY: 0.158 AC XY: 11736 AN XY: 74434

African (AFR) AF: 0.117 AC: 4854 AN: 41548

American (AMR) AF: 0.156 AC: 2387 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3468

East Asian (EAS) AF: 0.00945 AC: 49 AN: 5184

South Asian (SAS) AF: 0.181 AC: 873 AN: 4820

European-Finnish (FIN) AF: 0.190 AC: 2012 AN: 10584

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13166 AN: 68014

Other (OTH) AF: 0.167 AC: 351 AN: 2108

Alfa AF: 0.183 Hom.: 5307

Bravo AF: 0.154

Asia WGS AF: 0.0910 AC: 316 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.7
DANN	Benign	0.59
PhyloP100		0.073
Mutation Taster		=100/0	polymorphism (auto)

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: rs701755; hg19: chr3-148902714;