10-74138229-T-C

Variant names:

• chr10-74138229-T-C
• rs775092470
• NM_012095.6:c.151A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_012095.6(AP3M1):​c.151A>G​(p.Thr51Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: AP3M1 NM_012095.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

Genes affected

AP3M1 (HGNC:569): (adaptor related protein complex 3 subunit mu 1) The protein encoded by this gene is the medium subunit of AP-3, which is an adaptor-related protein complex associated with the Golgi region as well as more peripheral intracellular structures. AP-3 facilitates the budding of vesicles from the Golgi membrane, and it may directly function in protein sorting to the endosomal/lysosomal system. AP-3 is a heterotetrameric protein complex composed of two large subunits (delta and beta3), a medium subunit (mu3), and a small subunit (sigma 3). Mutations in one of the large subunits of AP-3 have been associated with the Hermansky-Pudlak syndrome, a genetic disorder characterized by defective lysosome-related organelles. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3999627).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012095.6. 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
	AP3M1	NM_012095.6	MANE Select	c.151A>G	p.Thr51Ala	missense	Exon 2 of 9	NP_036227.1	Q9Y2T2
	AP3M1	NM_001320263.2		c.151A>G	p.Thr51Ala	missense	Exon 4 of 11	NP_001307192.1	Q9Y2T2
	AP3M1	NM_001320264.2		c.151A>G	p.Thr51Ala	missense	Exon 2 of 9	NP_001307193.1	Q9Y2T2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3M1	ENST00000355264.9	TSL:1 MANE Select	c.151A>G	p.Thr51Ala	missense	Exon 2 of 9	ENSP00000347408.4	Q9Y2T2
	AP3M1	ENST00000372745.1	TSL:1	c.151A>G	p.Thr51Ala	missense	Exon 3 of 10	ENSP00000361831.1	Q9Y2T2
	AP3M1	ENST00000867215.1		c.151A>G	p.Thr51Ala	missense	Exon 3 of 10	ENSP00000537274.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000716 AC: 18 AN: 251474 AF XY: 0.0000883

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 727226

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74294

African (AFR) AF: 0.000169 AC: 7 AN: 41416

American (AMR) AF: 0.000131 AC: 2 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.079
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.53
Sift	Benign	0.11	T
Sift4G	Benign	0.29	T
Polyphen		0.041	B
Vest4		0.78
MutPred		0.50		Loss of glycosylation at T51 (P = 0.0394)
MVP		0.85
MPC		0.38
ClinPred		0.15	T
GERP RS		5.6
Varity_R		0.25
gMVP		0.65
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs775092470; hg19: chr10-75897987;