3-149178500-T-C

Variant names:

• chr3-149178500-T-C
• rs34987997
• NM_000096.4:c.2793A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000096.4(CP):​c.2793A>G​(p.Leu931Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,506 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (11 hom.)
• Consequence: CP NM_000096.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.44
• Publications: 2 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 -9 ACMG points.

• BP6: Variant 3-149178500-T-C is Benign according to our data. Variant chr3-149178500-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128840.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00212 (3093/1461188) while in subpopulation MID AF = 0.0165 (95/5764). AF 95% confidence interval is 0.0138. There are 11 homozygotes in GnomAdExome4. There are 1488 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD gene

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.2793A>G	p.Leu931Leu	synonymous	Exon 16 of 19	NP_000087.2
	CP	NR_046371.2		n.2617A>G		non_coding_transcript_exon	Exon 15 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.2793A>G	p.Leu931Leu	synonymous	Exon 16 of 19	ENSP00000264613.6
	CP	ENST00000494544.1	TSL:1	c.2142A>G	p.Leu714Leu	synonymous	Exon 13 of 16	ENSP00000420545.1
	CP	ENST00000460674.5	TSL:1	n.710A>G		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 281 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00202 AC: 507 AN: 251284 AF XY: 0.00182

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00310

Gnomad NFE exome AF: 0.00258

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00212 AC: 3093 AN: 1461188 Hom.: 11 Cov.: 31 AF XY: 0.00205 AC XY: 1488 AN XY: 726942

African (AFR) AF: 0.000359 AC: 12 AN: 33458

American (AMR) AF: 0.00242 AC: 108 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86244

European-Finnish (FIN) AF: 0.00290 AC: 155 AN: 53400

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5764

European-Non Finnish (NFE) AF: 0.00227 AC: 2525 AN: 1111418

Other (OTH) AF: 0.00199 AC: 120 AN: 60374

GnomAD4 genome AF: 0.00184 AC: 280 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.00183 AC XY: 136 AN XY: 74496

African (AFR) AF: 0.000385 AC: 16 AN: 41576

American (AMR) AF: 0.00340 AC: 52 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00216 AC: 23 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00254 AC: 173 AN: 68026

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00197 Hom.: 0

Bravo AF: 0.00216

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00308

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.82
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34987997; hg19: chr3-148896287;