Genetic Variant AP1M1:p.Gln132Arg (chr19-16208146-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032493.4(AP1M1):c.395A>G(p.Gln132Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,612,260 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

AP1M1
NM_032493.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.03

Variant links:

Genes affected

AP1M1 (HGNC:13667): (adaptor related protein complex 1 subunit mu 1) The protein encoded by this gene is the medium chain of the trans-Golgi network clathrin-associated protein complex AP-1. The other components of this complex are beta-prime-adaptin, gamma-adaptin, and the small chain AP1S1. This complex is located at the Golgi vesicle and links clathrin to receptors in coated vesicles. These vesicles are involved in endocytosis and Golgi processing. Alternatively spliced transcript variants encoding distinct protein isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

AP1M1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP1M1	NM_032493.4 link	c.395A>G	p.Gln132Arg	missense_variant	Exon 4 of 12	ENST00000291439.8	NP_115882.1	Q9BXS5-1A0A024R7K8B3KNH5
AP1M1	NM_001130524.2 link	c.395A>G	p.Gln132Arg	missense_variant	Exon 4 of 13		NP_001123996.1	Q9BXS5-2Q59EK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP1M1	ENST00000291439.8 link	c.395A>G	p.Gln132Arg	missense_variant	Exon 4 of 12	1	NM_032493.4	ENSP00000291439.2		Q9BXS5-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151876

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

250010

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135166

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1460384

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726550

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151876

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74154

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.395A>G (p.Q132R) alteration is located in exon 4 (coding exon 4) of the AP1M1 gene. This alteration results from a A to G substitution at nucleotide position 395, causing the glutamine (Q) at amino acid position 132 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Benign

0.89

DEOGEN2

Benign

0.25

T;.;T;.;.;.;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D

M_CAP

Benign

0.081

MetaRNN

Uncertain

0.47

T;T;T;T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.6

L;.;.;.;L;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.9

N;.;.;N;N;.;.

REVEL

Uncertain

0.39

Sift

Benign

0.37

T;.;.;T;T;.;.

Sift4G

Benign

0.29

T;T;T;T;T;T;T

Polyphen

0.93

P;.;.;B;.;.;.

Vest4

0.90

MutPred

0.38

Loss of methylation at K129 (P = 0.0932);Loss of methylation at K129 (P = 0.0932);.;Loss of methylation at K129 (P = 0.0932);Loss of methylation at K129 (P = 0.0932);.;.;

MVP

0.91

MPC

2.3

ClinPred

0.63

GERP RS

3.9

Varity_R

0.29

gMVP

0.81

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over