chr3-149167992-A-ATT

Variant names:

• chr3-149167992-A-ATT
• rs397710976
• NM_032383.5:c.2887+18_2887+19dupTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_032383.5(HPS3):​c.2887+18_2887+19dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0069 (8 hom., cov: 0)
  • Exomes 𝑓: 0.010 (18 hom.)
• Consequence: HPS3 NM_032383.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.188
• Publications: 0 publications found

Genes affected

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]

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 -10 ACMG points.

• BP6: Variant 3-149167992-A-ATT is Benign according to our data. Variant chr3-149167992-A-ATT is described in ClinVar as Benign. ClinVar VariationId is 1169104.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00695 (1045/150398) while in subpopulation SAS AF = 0.0198 (95/4788). AF 95% confidence interval is 0.0166. There are 8 homozygotes in GnomAd4. There are 540 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032383.5. 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
	HPS3	NM_032383.5	MANE Select	c.2887+18_2887+19dupTT		intron	N/A	NP_115759.2
	HPS3	NM_001308258.2		c.2392+18_2392+19dupTT		intron	N/A	NP_001295187.1	G5E9V4
	CP	NR_046371.2		n.2843-1944_2843-1943dupAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS3	ENST00000296051.7	TSL:1 MANE Select	c.2887+18_2887+19dupTT		intron	N/A	ENSP00000296051.2	Q969F9-1
	HPS3	ENST00000870872.1		c.2872+18_2872+19dupTT		intron	N/A	ENSP00000540931.1
	HPS3	ENST00000870871.1		c.2833+18_2833+19dupTT		intron	N/A	ENSP00000540930.1

Frequencies

GnomAD3 genomes AF: 0.00695 AC: 1045 AN: 150284 Hom.: 8 Cov.: 0

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00186

Gnomad ASJ AF: 0.00378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0200

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00966

Gnomad OTH AF: 0.00388

GnomAD2 exomes AF: 0.00988 AC: 2036 AN: 206140 AF XY: 0.0105

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00732

Gnomad EAS exome AF: 0.000328

Gnomad FIN exome AF: 0.0179

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0100

GnomAD4 exome AF: 0.0101 AC: 11520 AN: 1137512 Hom.: 18 Cov.: 18 AF XY: 0.0105 AC XY: 6037 AN XY: 577410

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00763 AC: 178 AN: 23342

American (AMR) AF: 0.00175 AC: 72 AN: 41120

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 133 AN: 23048

East Asian (EAS) AF: 0.000678 AC: 24 AN: 35396

South Asian (SAS) AF: 0.0185 AC: 1405 AN: 75742

European-Finnish (FIN) AF: 0.0164 AC: 824 AN: 50272

Middle Eastern (MID) AF: 0.00668 AC: 33 AN: 4940

European-Non Finnish (NFE) AF: 0.0101 AC: 8397 AN: 835042

Other (OTH) AF: 0.00934 AC: 454 AN: 48610

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00695 AC: 1045 AN: 150398 Hom.: 8 Cov.: 0 AF XY: 0.00736 AC XY: 540 AN XY: 73418

African (AFR) AF: 0.00185 AC: 76 AN: 41042

American (AMR) AF: 0.00186 AC: 28 AN: 15084

Ashkenazi Jewish (ASJ) AF: 0.00378 AC: 13 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.0198 AC: 95 AN: 4788

European-Finnish (FIN) AF: 0.0168 AC: 172 AN: 10238

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.00966 AC: 651 AN: 67404

Other (OTH) AF: 0.00384 AC: 8 AN: 2082

Alfa AF: 0.00835 Hom.: 479

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hermansky-Pudlak syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs397710976; hg19: chr3-148885779;