19-10579804-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005498.5(AP1M2):​c.728G>A​(p.Arg243Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

AP1M2
NM_005498.5 missense

Scores

6
6
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.80
Variant links:
Genes affected
AP1M2 (HGNC:558): (adaptor related protein complex 1 subunit mu 2) This gene encodes a subunit of the heterotetrameric adaptor-related protein comlex 1 (AP-1), which belongs to the adaptor complexes medium subunits family. This protein is capable of interacting with tyrosine-based sorting signals. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AP1M2NM_005498.5 linkc.728G>A p.Arg243Gln missense_variant Exon 7 of 12 ENST00000250244.11 NP_005489.2 Q9Y6Q5-1
AP1M2NM_001300887.2 linkc.734G>A p.Arg245Gln missense_variant Exon 7 of 12 NP_001287816.1 Q9Y6Q5-2Q53GI5
AP1M2XM_047438018.1 linkc.656G>A p.Arg219Gln missense_variant Exon 7 of 12 XP_047293974.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AP1M2ENST00000250244.11 linkc.728G>A p.Arg243Gln missense_variant Exon 7 of 12 1 NM_005498.5 ENSP00000250244.5 Q9Y6Q5-1
AP1M2ENST00000590923.5 linkc.734G>A p.Arg245Gln missense_variant Exon 7 of 12 1 ENSP00000465685.1 Q9Y6Q5-2
AP1M2ENST00000591240.5 linkc.491G>A p.Arg164Gln missense_variant Exon 5 of 7 3 ENSP00000465193.1 K7EJJ1
AP1M2ENST00000589684.5 linkc.650G>A p.Arg217Gln missense_variant Exon 7 of 7 3 ENSP00000467498.1 K7EPR4

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152122
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
249180
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135046
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000872
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:
0.00000886
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461242
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
726862
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000505
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152122
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74296
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 21, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.728G>A (p.R243Q) alteration is located in exon 7 (coding exon 7) of the AP1M2 gene. This alteration results from a G to A substitution at nucleotide position 728, causing the arginine (R) at amino acid position 243 to be replaced by a glutamine (Q). 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
Pathogenic
0.83
BayesDel_addAF
Benign
-0.036
T
BayesDel_noAF
Benign
-0.090
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.19
.;T;.;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;D;D;D
M_CAP
Benign
0.025
D
MetaRNN
Pathogenic
0.79
D;D;D;D
MetaSVM
Benign
-0.83
T
MutationAssessor
Pathogenic
3.1
.;M;.;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-3.8
.;D;.;.
REVEL
Uncertain
0.38
Sift
Benign
0.051
.;T;.;.
Sift4G
Uncertain
0.040
D;D;.;.
Polyphen
0.93
P;D;.;.
Vest4
0.83
MutPred
0.76
.;Loss of sheet (P = 0.0817);.;.;
MVP
0.34
MPC
0.69
ClinPred
0.90
D
GERP RS
5.2
Varity_R
0.45
gMVP
0.46

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs1490195492; hg19: chr19-10690480; API