rs1554059568

Variant names:

• chr5-78039087-T-C
• rs1554059568
• NM_003664.5:c.2765A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003664.5(AP3B1):​c.2765A>G​(p.Lys922Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AP3B1 NM_003664.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• Publications: 0 publications found

Genes affected

AP3B1 (HGNC:566): (adaptor related protein complex 3 subunit beta 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is part of the heterotetrameric AP-3 protein complex which interacts with the scaffolding protein clathrin. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2012]

AP3B1 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08183706).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003664.5. 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
	AP3B1	NM_003664.5	MANE Select	c.2765A>G	p.Lys922Arg	missense	Exon 23 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.2618A>G	p.Lys873Arg	missense	Exon 23 of 27	NP_001258698.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.2765A>G	p.Lys922Arg	missense	Exon 23 of 27	ENSP00000255194.7
	AP3B1	ENST00000519295.7	TSL:1	c.2618A>G	p.Lys873Arg	missense	Exon 23 of 27	ENSP00000430597.1
	AP3B1	ENST00000913629.1		c.2765A>G	p.Lys922Arg	missense	Exon 23 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hermansky-Pudlak syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.040
Sift	Benign	0.34	T
Sift4G	Benign	0.21	T
Polyphen		0.0020	B
Vest4		0.24
MutPred		0.25		Loss of methylation at K922 (P = 0.0163)
MVP		0.44
MPC		0.075
ClinPred		0.12	T
GERP RS		3.0
PromoterAI		0.0023	Neutral
Varity_R		0.046
gMVP		0.15
Mutation Taster		=99/1	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: rs1554059568; hg19: chr5-77334911;