3-149177867-A-G

Variant names:

• chr3-149177867-A-G
• rs34394958
• NM_000096.4:c.2991T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000096.4(CP):​c.2991T>C​(p.His997His) 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:9
• Conservation: PhyloP100: 0.990
• Publications: 10 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Ambry Genetics, Orphanet
• 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=-0.56).
• BP6: Variant 3-149177867-A-G is Benign according to our data. Variant chr3-149177867-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 98 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.2991T>C	p.His997His	synonymous	Exon 17 of 19	NP_000087.2	P00450
	CP	NR_046371.2		n.2815T>C		non_coding_transcript_exon	Exon 16 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.2991T>C	p.His997His	synonymous	Exon 17 of 19	ENSP00000264613.6	P00450
	CP	ENST00000494544.1	TSL:1	c.2340T>C	p.His780His	synonymous	Exon 14 of 16	ENSP00000420545.1	H7C5R1
	CP	ENST00000460674.5	TSL:1	n.908T>C		non_coding_transcript_exon	Exon 3 of 5

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

GnomAD2 exomes AF: 0.0334 AC: 8405 AN: 251326 AF XY: 0.0354

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 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

African (AFR) AF: 0.00828 AC: 277 AN: 33462

American (AMR) AF: 0.0160 AC: 715 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 348 AN: 26126

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39684

South Asian (SAS) AF: 0.0349 AC: 3008 AN: 86246

European-Finnish (FIN) AF: 0.0628 AC: 3356 AN: 53412

Middle Eastern (MID) AF: 0.0522 AC: 301 AN: 5768

European-Non Finnish (NFE) AF: 0.0471 AC: 52357 AN: 1111288

Other (OTH) AF: 0.0348 AC: 2098 AN: 60368

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

African (AFR) AF: 0.00965 AC: 401 AN: 41570

American (AMR) AF: 0.0201 AC: 307 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0303 AC: 146 AN: 4822

European-Finnish (FIN) AF: 0.0613 AC: 651 AN: 10612

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0441 AC: 2997 AN: 68022

Other (OTH) AF: 0.0274 AC: 58 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Deficiency of ferroxidase (2)
-	-	1	Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.1
DANN	Benign	0.74
PhyloP100		0.99
Mutation Taster		=100/0	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: rs34394958; hg19: chr3-148895654;