3-149177867-A-G

Position:

• chr3-149177867-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000096.4(CP):​c.2991T>C​(p.His997=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0416 in 1,613,350 control chromosomes in the GnomAD database, including 1,660 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (98 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1562 hom.)
• Consequence: CP NM_000096.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.990

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 3-149177867-A-G is Benign according to our data. Variant chr3-149177867-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-149177867-A-G is described in Lovd as [Benign]. Variant chr3-149177867-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0304 (4625/152276) while in subpopulation NFE AF= 0.0441 (2997/68022). AF 95% confidence interval is 0.0427. There are 98 homozygotes in gnomad4. There are 2290 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 98 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CP	NM_000096.4	c.2991T>C	p.His997=	synonymous_variant	17/19	ENST00000264613.11	NP_000087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CP	ENST00000264613.11	c.2991T>C	p.His997=	synonymous_variant	17/19	1	NM_000096.4	ENSP00000264613	P1

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4628 AN: 152158 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.00965

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0305

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0441

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0334 AC: 8405 AN: 251326 Hom.: 191 AF XY: 0.0354 AC XY: 4815 AN XY: 135830

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0339

Gnomad FIN exome AF: 0.0645

Gnomad NFE exome AF: 0.0434

Gnomad OTH exome AF: 0.0377

GnomAD4 exome AF: 0.0428 AC: 62464 AN: 1461074 Hom.: 1562 Cov.: 31 AF XY: 0.0426 AC XY: 30940 AN XY: 726854

Gnomad4 AFR exome AF: 0.00828

Gnomad4 AMR exome AF: 0.0160

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0349

Gnomad4 FIN exome AF: 0.0628

Gnomad4 NFE exome AF: 0.0471

Gnomad4 OTH exome AF: 0.0348

GnomAD4 genome AF: 0.0304 AC: 4625 AN: 152276 Hom.: 98 Cov.: 32 AF XY: 0.0308 AC XY: 2290 AN XY: 74450

Gnomad4 AFR AF: 0.00965

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0303

Gnomad4 FIN AF: 0.0613

Gnomad4 NFE AF: 0.0441

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0376 Hom.: 76

Bravo AF: 0.0267

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0412

EpiControl AF: 0.0431

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 06, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Deficiency of ferroxidase Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Hermansky-Pudlak syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.1
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs34394958; hg19: chr3-148895654;