rs1053709

Variant names:

• chr3-149186647-T-G
• rs1053709
• NM_000096.4:c.1950A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000096.4(CP):​c.1950A>C​(p.Gly650Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0556 in 1,614,152 control chromosomes in the GnomAD database, including 2,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (191 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2641 hom.)
• Consequence: CP NM_000096.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.733
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 3-149186647-T-G is Benign according to our data. Variant chr3-149186647-T-G is described in ClinVar as Benign. ClinVar VariationId is 128838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.733 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0641 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.1950A>C	p.Gly650Gly	synonymous	Exon 11 of 19	NP_000087.2
	CP	NR_046371.2		n.1902-1201A>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.1950A>C	p.Gly650Gly	synonymous	Exon 11 of 19	ENSP00000264613.6
	CP	ENST00000494544.1	TSL:1	c.1299A>C	p.Gly433Gly	synonymous	Exon 8 of 16	ENSP00000420545.1
	CP	ENST00000489736.5	TSL:1	n.1175A>C		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.0417 AC: 6344 AN: 152186 Hom.: 191 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0270

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0657

Gnomad OTH AF: 0.0546

GnomAD2 exomes AF: 0.0441 AC: 11080 AN: 251428 AF XY: 0.0453

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0680

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0295

Gnomad NFE exome AF: 0.0639

Gnomad OTH exome AF: 0.0575

GnomAD4 exome AF: 0.0571 AC: 83456 AN: 1461848 Hom.: 2641 Cov.: 31 AF XY: 0.0564 AC XY: 41030 AN XY: 727234

African (AFR) AF: 0.0111 AC: 373 AN: 33480

American (AMR) AF: 0.0297 AC: 1330 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0703 AC: 1837 AN: 26136

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39700

South Asian (SAS) AF: 0.0335 AC: 2893 AN: 86256

European-Finnish (FIN) AF: 0.0322 AC: 1719 AN: 53420

Middle Eastern (MID) AF: 0.0662 AC: 382 AN: 5768

European-Non Finnish (NFE) AF: 0.0643 AC: 71483 AN: 1111968

Other (OTH) AF: 0.0568 AC: 3429 AN: 60396

GnomAD4 genome AF: 0.0417 AC: 6346 AN: 152304 Hom.: 191 Cov.: 32 AF XY: 0.0401 AC XY: 2983 AN XY: 74476

African (AFR) AF: 0.0119 AC: 494 AN: 41568

American (AMR) AF: 0.0396 AC: 606 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 215 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5192

South Asian (SAS) AF: 0.0255 AC: 123 AN: 4820

European-Finnish (FIN) AF: 0.0270 AC: 287 AN: 10624

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0657 AC: 4467 AN: 68022

Other (OTH) AF: 0.0541 AC: 114 AN: 2108

Alfa AF: 0.0560 Hom.: 517

Bravo AF: 0.0413

Asia WGS AF: 0.0190 AC: 70 AN: 3478

EpiCase AF: 0.0638

EpiControl AF: 0.0671

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Deficiency of ferroxidase (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.4
DANN	Benign	0.70
PhyloP100		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	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: rs1053709; hg19: chr3-148904434; COSMIC: COSV107278638; COSMIC: COSV107278638;