19-10581591-G-A

Variant summary

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

The NM_005498.5(AP1M2):​c.442C>T​(p.Arg148Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,461,576 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: not found (cov: 31)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

AP1M2
NM_005498.5 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.15
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, 0.762

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AP1M2NM_005498.5 linkuse as main transcriptc.442C>T p.Arg148Trp missense_variant 5/12 ENST00000250244.11 NP_005489.2 Q9Y6Q5-1
AP1M2NM_001300887.2 linkuse as main transcriptc.442C>T p.Arg148Trp missense_variant 5/12 NP_001287816.1 Q9Y6Q5-2Q53GI5
AP1M2XM_047438018.1 linkuse as main transcriptc.364C>T p.Arg122Trp missense_variant 5/12 XP_047293974.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AP1M2ENST00000250244.11 linkuse as main transcriptc.442C>T p.Arg148Trp missense_variant 5/121 NM_005498.5 ENSP00000250244.5 Q9Y6Q5-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249114
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135080
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000166
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1461576
Hom.:
0
Cov.:
32
AF XY:
0.00000825
AC XY:
6
AN XY:
727054
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000312
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 17, 2024The c.442C>T (p.R148W) alteration is located in exon 5 (coding exon 5) of the AP1M2 gene. This alteration results from a C to T substitution at nucleotide position 442, causing the arginine (R) at amino acid position 148 to be replaced by a tryptophan (W). 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
0.30
BayesDel_addAF
Benign
-0.038
T
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
.;T;.;.;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.91
D;D;D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.76
D;D;D;D;D
MetaSVM
Uncertain
-0.092
T
MutationAssessor
Pathogenic
3.3
M;M;.;.;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-5.9
.;D;.;.;.
REVEL
Uncertain
0.30
Sift
Pathogenic
0.0
.;D;.;.;.
Sift4G
Uncertain
0.0020
D;D;.;.;D
Polyphen
0.99
D;D;.;.;.
Vest4
0.65
MutPred
0.46
Loss of disorder (P = 0.012);Loss of disorder (P = 0.012);.;.;.;
MVP
0.92
MPC
0.59
ClinPred
0.92
D
GERP RS
3.8
Varity_R
0.58
gMVP
0.36

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: rs542063701; hg19: chr19-10692267; API