rs34624984

Variant names:

• chr3-149206277-G-A
• rs34624984
• NM_000096.4:c.1099C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000096.4(CP):​c.1099C>T​(p.Arg367Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,613,912 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R367H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (31 hom.)
• Consequence: CP NM_000096.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0320
• Publications: 7 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 (MetaRNN=0.0047535).
• BP6: Variant 3-149206277-G-A is Benign according to our data. Variant chr3-149206277-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0135 (2048/152176) while in subpopulation AFR AF = 0.0454 (1884/41512). AF 95% confidence interval is 0.0437. There are 47 homozygotes in GnomAd4. There are 986 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CP	NM_000096.4	c.1099C>T	p.Arg367Cys	missense_variant	Exon 6 of 19	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11	c.1099C>T	p.Arg367Cys	missense_variant	Exon 6 of 19	1	NM_000096.4	ENSP00000264613.6

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2048 AN: 152058 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00793

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00350 AC: 879 AN: 251218 AF XY: 0.00247

Gnomad AFR exome AF: 0.0426

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00141 AC: 2059 AN: 1461736 Hom.: 31 Cov.: 31 AF XY: 0.00122 AC XY: 889 AN XY: 727170

African (AFR) AF: 0.0433 AC: 1451 AN: 33476

American (AMR) AF: 0.00347 AC: 155 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.000200 AC: 222 AN: 1111884

Other (OTH) AF: 0.00331 AC: 200 AN: 60388

GnomAD4 genome AF: 0.0135 AC: 2048 AN: 152176 Hom.: 47 Cov.: 32 AF XY: 0.0133 AC XY: 986 AN XY: 74400

African (AFR) AF: 0.0454 AC: 1884 AN: 41512

American (AMR) AF: 0.00792 AC: 121 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68008

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00494 Hom.: 31

Bravo AF: 0.0148

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0445 AC: 196

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00415 AC: 504

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of ferroxidase Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 18, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

not specified Benign:1

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.047	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.25	.;T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Uncertain	0.53	D
PhyloP100		0.032
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.090	T;T
Sift4G	Uncertain	0.053	T;T
Vest4		0.24
MVP		0.82
MPC		0.21
ClinPred		0.011	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.80
Mutation Taster		=97/3	polymorphism

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: rs34624984; hg19: chr3-148924064;