rs7706167

Variant names:

• chr5-78228180-T-G
• rs7706167
• NM_003664.5:c.339A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003664.5(AP3B1):​c.339A>C​(p.Ala113Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,611,866 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (55 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (48 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.88
• Publications: 1 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 5-78228180-T-G is Benign according to our data. Variant chr5-78228180-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.88 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0136 (2073/152228) while in subpopulation AFR AF = 0.0473 (1966/41524). AF 95% confidence interval is 0.0456. There are 55 homozygotes in GnomAd4. There are 1015 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 55 AR gene

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.339A>C	p.Ala113Ala	synonymous	Exon 4 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.192A>C	p.Ala64Ala	synonymous	Exon 4 of 27	NP_001258698.1
	AP3B1	NM_001410752.1		c.339A>C	p.Ala113Ala	synonymous	Exon 4 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.339A>C	p.Ala113Ala	synonymous	Exon 4 of 27	ENSP00000255194.7
	AP3B1	ENST00000519295.7	TSL:1	c.192A>C	p.Ala64Ala	synonymous	Exon 4 of 27	ENSP00000430597.1
	AP3B1	ENST00000913629.1		c.339A>C	p.Ala113Ala	synonymous	Exon 4 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2063 AN: 152110 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0472

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00369 AC: 920 AN: 248998 AF XY: 0.00274

Gnomad AFR exome AF: 0.0503

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00144 AC: 2102 AN: 1459638 Hom.: 48 Cov.: 30 AF XY: 0.00129 AC XY: 938 AN XY: 726110

African (AFR) AF: 0.0498 AC: 1659 AN: 33318

American (AMR) AF: 0.00216 AC: 96 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.000186 AC: 16 AN: 85932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53092

Middle Eastern (MID) AF: 0.00608 AC: 35 AN: 5758

European-Non Finnish (NFE) AF: 0.0000999 AC: 111 AN: 1111222

Other (OTH) AF: 0.00307 AC: 185 AN: 60284

GnomAD4 genome AF: 0.0136 AC: 2073 AN: 152228 Hom.: 55 Cov.: 32 AF XY: 0.0136 AC XY: 1015 AN XY: 74444

African (AFR) AF: 0.0473 AC: 1966 AN: 41524

American (AMR) AF: 0.00412 AC: 63 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68002

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00696 Hom.: 9

Bravo AF: 0.0156

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000165

EpiControl AF: 0.000179

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hermansky-Pudlak syndrome 2 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.2
DANN	Benign	0.64
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7706167; hg19: chr5-77524004;