3-149173734-T-C

Variant names:

• chr3-149173734-T-C
• rs34272112
• NM_000096.4:c.3182-4A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000096.4(CP):​c.3182-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,416,672 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (3 hom.)
• Consequence: CP NM_000096.4 splice_region, intron
• Scores: Splicing: ADA: 0.001273
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.599
• Publications: 1 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]

HPS3 (HGNC:15597): (HPS3 biogenesis of lysosomal organelles complex 2 subunit 1) This gene encodes a protein containing a potential clathrin-binding motif, consensus dileucine signals, and tyrosine-based sorting signals for targeting to vesicles of lysosomal lineage. The encoded protein may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 3. [provided by RefSeq, Apr 2015]

HPS3 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Hermansky-Pudlak syndrome without pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 3-149173734-T-C is Benign according to our data. Variant chr3-149173734-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128842.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 = 0.00757 (1152/152216) while in subpopulation AFR AF = 0.0254 (1055/41550). AF 95% confidence interval is 0.0241. There are 13 homozygotes in GnomAd4. There are 561 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.3182-4A>G		splice_region intron	N/A	NP_000087.2
	CP	NR_046371.2		n.2842+4106A>G		intron	N/A
	HPS3	NM_032383.5	MANE Select	c.*1512T>C		downstream_gene	N/A	NP_115759.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.3182-4A>G		splice_region intron	N/A	ENSP00000264613.6
	CP	ENST00000494544.1	TSL:1	c.2543-4A>G		splice_region intron	N/A	ENSP00000420545.1
	CP	ENST00000460674.5	TSL:1	n.1038-4A>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00753 AC: 1146 AN: 152098 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00197 AC: 353 AN: 178860 AF XY: 0.00154

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.000344

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.000781 AC: 988 AN: 1264456 Hom.: 3 Cov.: 20 AF XY: 0.000710 AC XY: 448 AN XY: 631420

African (AFR) AF: 0.0204 AC: 588 AN: 28758

American (AMR) AF: 0.00195 AC: 74 AN: 37980

Ashkenazi Jewish (ASJ) AF: 0.000374 AC: 9 AN: 24046

East Asian (EAS) AF: 0.00 AC: 0 AN: 36504

South Asian (SAS) AF: 0.000148 AC: 11 AN: 74450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49640

Middle Eastern (MID) AF: 0.00205 AC: 9 AN: 4386

European-Non Finnish (NFE) AF: 0.000163 AC: 156 AN: 955688

Other (OTH) AF: 0.00266 AC: 141 AN: 53004

GnomAD4 genome AF: 0.00757 AC: 1152 AN: 152216 Hom.: 13 Cov.: 32 AF XY: 0.00754 AC XY: 561 AN XY: 74434

African (AFR) AF: 0.0254 AC: 1055 AN: 41550

American (AMR) AF: 0.00471 AC: 72 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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: 0.000177 AC: 12 AN: 67968

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00342 Hom.: 1

Bravo AF: 0.00882

Asia WGS AF: 0.00203 AC: 7 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.010
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: rs34272112; hg19: chr3-148891521;