19-2102258-G-C

Variant names:

• chr19-2102258-G-C
• rs776007925
• NM_001261826.3:c.3563C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001261826.3(AP3D1):​c.3563C>G​(p.Ser1188Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000383 in 1,460,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: AP3D1 NM_001261826.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.82
• Publications: 0 publications found

Genes affected

AP3D1 (HGNC:568): (adaptor related protein complex 3 subunit delta 1) The protein encoded by this gene is a subunit of the AP3 adaptor-like complex, which is not clathrin-associated, but is associated with the golgi region, as well as more peripheral structures. The AP-3 complex facilitates the budding of vesicles from the golgi membrane, and may be directly involved in trafficking to lysosomes. This subunit is implicated in intracellular biogenesis and trafficking of pigment granules, and possibly platelet dense granules and neurotransmitter vesicles. Defects in this gene are a cause of a new type of Hermansky-Pudlak syndrome. [provided by RefSeq, Feb 2017]

AP3D1 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 10

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001261826.3. 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
	AP3D1	NM_001261826.3	MANE Select	c.3563C>G	p.Ser1188Cys	missense	Exon 32 of 32	NP_001248755.1	O14617-5
	AP3D1	NM_001374799.1		c.3527C>G	p.Ser1176Cys	missense	Exon 32 of 32	NP_001361728.1	A0A8V8TQW4
	AP3D1	NM_003938.8		c.3377C>G	p.Ser1126Cys	missense	Exon 30 of 30	NP_003929.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3D1	ENST00000643116.3	MANE Select	c.3563C>G	p.Ser1188Cys	missense	Exon 32 of 32	ENSP00000495274.2	O14617-5
	AP3D1	ENST00000345016.9	TSL:1	c.3377C>G	p.Ser1126Cys	missense	Exon 30 of 30	ENSP00000344055.4	O14617-1
	AP3D1	ENST00000591650.1	TSL:1	n.800C>G		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000242 AC: 6 AN: 247882 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000537

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1460970 Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26 AN XY: 726864

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111284

Other (OTH) AF: 0.0000497 AC: 3 AN: 60368

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Benign	0.88
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.28
Sift	Benign	0.031	D
Sift4G	Uncertain	0.053	T
Polyphen		0.99	D
Vest4		0.50
MutPred		0.66		Loss of disorder (P = 0.0092)
MVP		0.33
MPC		0.38
ClinPred		0.55	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.33
Mutation Taster		=86/14	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: rs776007925; hg19: chr19-2102257;