NM_003664.5:c.2613C>T

Variant names:

• chr5-78039239-G-A
• rs144420604
• NM_003664.5:c.2613C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_003664.5(AP3B1):​c.2613C>T​(p.His871His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,614,106 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (26 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.214
• Publications: 3 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 5-78039239-G-A is Benign according to our data. Variant chr5-78039239-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210188.
• BP7: Synonymous conserved (PhyloP=0.214 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0031 (472/152274) while in subpopulation SAS AF = 0.00766 (37/4830). AF 95% confidence interval is 0.00571. There are 2 homozygotes in GnomAd4. There are 228 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.2613C>T	p.His871His	synonymous	Exon 23 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.2466C>T	p.His822His	synonymous	Exon 23 of 27	NP_001258698.1	O00203-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.2613C>T	p.His871His	synonymous	Exon 23 of 27	ENSP00000255194.7	O00203-1
	AP3B1	ENST00000519295.7	TSL:1	c.2466C>T	p.His822His	synonymous	Exon 23 of 27	ENSP00000430597.1	O00203-3
	AP3B1	ENST00000913629.1		c.2613C>T	p.His871His	synonymous	Exon 23 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152156 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00391 AC: 984 AN: 251442 AF XY: 0.00436

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00564

Gnomad NFE exome AF: 0.00452

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00467 AC: 6824 AN: 1461832 Hom.: 26 Cov.: 31 AF XY: 0.00480 AC XY: 3491 AN XY: 727216

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.00172 AC: 77 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39686

South Asian (SAS) AF: 0.00863 AC: 744 AN: 86258

European-Finnish (FIN) AF: 0.00507 AC: 271 AN: 53416

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.00489 AC: 5437 AN: 1111976

Other (OTH) AF: 0.00396 AC: 239 AN: 60392

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152274 Hom.: 2 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74458

African (AFR) AF: 0.000650 AC: 27 AN: 41560

American (AMR) AF: 0.00262 AC: 40 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4830

European-Finnish (FIN) AF: 0.00500 AC: 53 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00451 AC: 307 AN: 68014

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00279 Hom.: 1

Bravo AF: 0.00260

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00427

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autoinflammatory syndrome (1)
-	1	-	Hermansky-Pudlak syndrome (1)
-	-	1	Hermansky-Pudlak syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.48
DANN	Benign	0.79
PhyloP100		0.21
PromoterAI		0.028	Neutral
Mutation Taster		=96/4	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: rs144420604; hg19: chr5-77335063;