rs6453373

Variant names:

• chr5-78129204-A-G
• rs6453373
• NM_003664.5:c.1754T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-78129204-A-G
• chr5-78129204-A-T

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.1754T>C​(p.Val585Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V585E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: AP3B1 NM_003664.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.29
• Publications: 43 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=0.13772932).

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.1754T>C	p.Val585Ala	missense	Exon 16 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.1607T>C	p.Val536Ala	missense	Exon 16 of 27	NP_001258698.1
	AP3B1	NM_001410752.1		c.1754T>C	p.Val585Ala	missense	Exon 16 of 23	NP_001397681.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.1754T>C	p.Val585Ala	missense	Exon 16 of 27	ENSP00000255194.7
	AP3B1	ENST00000519295.7	TSL:1	c.1607T>C	p.Val536Ala	missense	Exon 16 of 27	ENSP00000430597.1
	AP3B1	ENST00000913629.1		c.1754T>C	p.Val585Ala	missense	Exon 16 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461138 Hom.: 0 Cov.: 45 AF XY: 0.00000275 AC XY: 2 AN XY: 726894

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

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

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111458

Other (OTH) AF: 0.0000331 AC: 2 AN: 60358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00383038), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 16608

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	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		6.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	1.5	N
REVEL	Benign	0.13
Sift	Benign	0.24	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.41		Loss of stability (P = 0.0154)
MVP		0.23
MPC		0.049
ClinPred		0.55	D
GERP RS		5.4
Varity_R		0.065
gMVP		0.32
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs6453373; hg19: chr5-77425028;