3-149167992-ATT-AT

Variant names:

• chr3-149167992-AT-A
• rs397710976
• NM_032383.5:c.2887+19delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

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

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: HPS3 NM_032383.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 3-149167992-AT-A is Benign according to our data. Variant chr3-149167992-AT-A is described in ClinVar as Benign. ClinVar VariationId is 774850.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS3	NM_032383.5	c.2887+19delT		intron_variant	Intron 16 of 16	ENST00000296051.7	NP_115759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS3	ENST00000296051.7	c.2887+19delT		intron_variant	Intron 16 of 16	1	NM_032383.5	ENSP00000296051.2

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150268 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00104 AC: 214 AN: 206140 AF XY: 0.00115

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.000946

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.000917

Gnomad FIN exome AF: 0.000152

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.000409

GnomAD4 exome AF: 0.00234 AC: 2636 AN: 1128202 Hom.: 0 Cov.: 18 AF XY: 0.00211 AC XY: 1210 AN XY: 572546

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

African (AFR) AF: 0.00106 AC: 25 AN: 23538

American (AMR) AF: 0.000867 AC: 35 AN: 40360

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 33 AN: 22644

East Asian (EAS) AF: 0.000685 AC: 24 AN: 35054

South Asian (SAS) AF: 0.00121 AC: 91 AN: 75096

European-Finnish (FIN) AF: 0.000280 AC: 14 AN: 49982

Middle Eastern (MID) AF: 0.00288 AC: 14 AN: 4864

European-Non Finnish (NFE) AF: 0.00279 AC: 2313 AN: 828476

Other (OTH) AF: 0.00181 AC: 87 AN: 48188

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150268 Hom.: 0 Cov.: 0 AF XY: 0.0000136 AC XY: 1 AN XY: 73284

African (AFR) AF: 0.00 AC: 0 AN: 40924

American (AMR) AF: 0.00 AC: 0 AN: 15058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67406

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.00955 Hom.: 479

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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

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: rs397710976; hg19: chr3-148885779; COSMIC: COSV52830276; COSMIC: COSV52830276;