chr3-149198428-G-A

Variant names:

• chr3-149198428-G-A
• rs61733458
• NM_000096.4:c.1652C>T

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.1652C>T​(p.Thr551Ile) variant causes a missense change. The variant allele was found at a frequency of 0.031 in 1,612,482 control chromosomes in the GnomAD database, including 978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (65 hom., cov: 32)
  • Exomes 𝑓: 0.032 (913 hom.)
• Consequence: CP NM_000096.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:13
• Conservation: PhyloP100: 6.57
• Publications: 15 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=0.01101324).
• BP6: Variant 3-149198428-G-A is Benign according to our data. Variant chr3-149198428-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0549 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.1652C>T	p.Thr551Ile	missense	Exon 9 of 19	NP_000087.2
	CP	NR_046371.2		n.1689C>T		non_coding_transcript_exon	Exon 9 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.1652C>T	p.Thr551Ile	missense	Exon 9 of 19	ENSP00000264613.6
	CP	ENST00000494544.1	TSL:1	c.1001C>T	p.Thr334Ile	missense	Exon 6 of 16	ENSP00000420545.1
	CP	ENST00000489736.5	TSL:1	n.877C>T		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3460 AN: 152130 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.00655

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.0610

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0326

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0285 AC: 7148 AN: 251032 AF XY: 0.0311

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.0326

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0307

Gnomad OTH exome AF: 0.0304

GnomAD4 exome AF: 0.0319 AC: 46572 AN: 1460234 Hom.: 913 Cov.: 30 AF XY: 0.0330 AC XY: 23995 AN XY: 726518

African (AFR) AF: 0.00568 AC: 190 AN: 33472

American (AMR) AF: 0.0170 AC: 762 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 783 AN: 26128

East Asian (EAS) AF: 0.00222 AC: 88 AN: 39694

South Asian (SAS) AF: 0.0646 AC: 5569 AN: 86180

European-Finnish (FIN) AF: 0.0235 AC: 1254 AN: 53412

Middle Eastern (MID) AF: 0.0472 AC: 272 AN: 5764

European-Non Finnish (NFE) AF: 0.0322 AC: 35770 AN: 1110522

Other (OTH) AF: 0.0312 AC: 1884 AN: 60346

GnomAD4 genome AF: 0.0227 AC: 3456 AN: 152248 Hom.: 65 Cov.: 32 AF XY: 0.0227 AC XY: 1691 AN XY: 74452

African (AFR) AF: 0.00655 AC: 272 AN: 41522

American (AMR) AF: 0.0191 AC: 292 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3472

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5184

South Asian (SAS) AF: 0.0606 AC: 292 AN: 4818

European-Finnish (FIN) AF: 0.0188 AC: 200 AN: 10612

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0326 AC: 2220 AN: 68018

Other (OTH) AF: 0.0256 AC: 54 AN: 2110

Alfa AF: 0.0271 Hom.: 15

Bravo AF: 0.0204

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.0301 AC: 259

ExAC AF: 0.0288 AC: 3498

Asia WGS AF: 0.0270 AC: 94 AN: 3478

EpiCase AF: 0.0316

EpiControl AF: 0.0305

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	6	Deficiency of ferroxidase (7)
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.57	D
PhyloP100		6.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.090
MPC		0.47
ClinPred		0.027	T
GERP RS		5.5
gMVP		0.90
Mutation Taster		=42/58	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: rs61733458; hg19: chr3-148916215;