10-74124451-G-A

Variant names:

• chr10-74124451-G-A
• NM_012095.6:c.1085C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012095.6(AP3M1):​c.1085C>T​(p.Ser362Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,502 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AP3M1 NM_012095.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35811514).

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.1085C>T	p.Ser362Phe	missense	Exon 8 of 9	NP_036227.1	Q9Y2T2
	AP3M1	NM_001320263.2		c.1085C>T	p.Ser362Phe	missense	Exon 10 of 11	NP_001307192.1	Q9Y2T2
	AP3M1	NM_001320264.2		c.1085C>T	p.Ser362Phe	missense	Exon 8 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.1085C>T	p.Ser362Phe	missense	Exon 8 of 9	ENSP00000347408.4	Q9Y2T2
	AP3M1	ENST00000372745.1	TSL:1	c.1085C>T	p.Ser362Phe	missense	Exon 9 of 10	ENSP00000361831.1	Q9Y2T2
	AP3M1	ENST00000867215.1		c.1085C>T	p.Ser362Phe	missense	Exon 9 of 10	ENSP00000537274.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461502 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727034

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111860

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

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	0.20
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.59	P
Vest4		0.37
MutPred		0.51		Loss of disorder (P = 0.0034)
MVP		0.33
MPC		0.78
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.49
gMVP		0.42
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr10-75884209;