NM_000096.4:c.3018+96C>G

Variant names:

• chr3-149177744-G-C
• rs17787768
• NM_000096.4:c.3018+96C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000096.4(CP):​c.3018+96C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,361,656 control chromosomes in the GnomAD database, including 6,293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (467 hom., cov: 32)
  • Exomes 𝑓: 0.089 (5826 hom.)
• Consequence: CP NM_000096.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0900
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-149177744-G-C is Benign according to our data. Variant chr3-149177744-G-C is described in ClinVar as Benign. ClinVar VariationId is 1257508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.19 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	NM_000096.4	MANE Select	c.3018+96C>G		intron	N/A	NP_000087.2
	CP	NR_046371.2		n.2842+96C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.3018+96C>G		intron	N/A	ENSP00000264613.6
	CP	ENST00000494544.1	TSL:1	c.2367+96C>G		intron	N/A	ENSP00000420545.1
	CP	ENST00000460674.5	TSL:1	n.935+96C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0644 AC: 9795 AN: 152070 Hom.: 465 Cov.: 32

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0630

Gnomad ASJ AF: 0.0749

Gnomad EAS AF: 0.00827

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.0390

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0906

Gnomad OTH AF: 0.0664

GnomAD4 exome AF: 0.0889 AC: 107510 AN: 1209468 Hom.: 5826 Cov.: 17 AF XY: 0.0932 AC XY: 57177 AN XY: 613716

African (AFR) AF: 0.0156 AC: 443 AN: 28436

American (AMR) AF: 0.0390 AC: 1722 AN: 44188

Ashkenazi Jewish (ASJ) AF: 0.0789 AC: 1934 AN: 24500

East Asian (EAS) AF: 0.00484 AC: 186 AN: 38428

South Asian (SAS) AF: 0.202 AC: 16259 AN: 80646

European-Finnish (FIN) AF: 0.0473 AC: 2489 AN: 52616

Middle Eastern (MID) AF: 0.0836 AC: 438 AN: 5240

European-Non Finnish (NFE) AF: 0.0902 AC: 79690 AN: 883396

Other (OTH) AF: 0.0836 AC: 4349 AN: 52018

GnomAD4 genome AF: 0.0644 AC: 9799 AN: 152188 Hom.: 467 Cov.: 32 AF XY: 0.0648 AC XY: 4822 AN XY: 74416

African (AFR) AF: 0.0193 AC: 800 AN: 41524

American (AMR) AF: 0.0628 AC: 960 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0749 AC: 260 AN: 3470

East Asian (EAS) AF: 0.00829 AC: 43 AN: 5186

South Asian (SAS) AF: 0.200 AC: 964 AN: 4816

European-Finnish (FIN) AF: 0.0390 AC: 413 AN: 10596

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0906 AC: 6160 AN: 68000

Other (OTH) AF: 0.0700 AC: 148 AN: 2114

Alfa AF: 0.0746 Hom.: 57

Bravo AF: 0.0578

Asia WGS AF: 0.0960 AC: 333 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.48
DANN	Benign	0.68
PhyloP100		-0.090
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: rs17787768; hg19: chr3-148895531;