Genetic Variant AP1M2:p.Gly350Arg (chr19-10575029-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005498.5(AP1M2):c.1048G>C(p.Gly350Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,502,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

AP1M2
NM_005498.5 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.76

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]

AP1M2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP1M2	NM_005498.5 link	c.1048G>C	p.Gly350Arg	missense_variant, splice_region_variant	Exon 10 of 12	ENST00000250244.11	NP_005489.2	Q9Y6Q5-1
AP1M2	NM_001300887.2 link	c.1054G>C	p.Gly352Arg	missense_variant, splice_region_variant	Exon 10 of 12		NP_001287816.1	Q9Y6Q5-2Q53GI5
AP1M2	XM_047438018.1 link	c.976G>C	p.Gly326Arg	missense_variant, splice_region_variant	Exon 10 of 12		XP_047293974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP1M2	ENST00000250244.11 link	c.1048G>C	p.Gly350Arg	missense_variant, splice_region_variant	Exon 10 of 12	1	NM_005498.5	ENSP00000250244.5		Q9Y6Q5-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000412

AC:

AN:

145500

Hom.:

AF XY:

0.0000387

AC XY:

AN XY:

77570

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000157

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:

0.0000446

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1350812

Hom.:

Cov.:

AF XY:

0.0000212

AC XY:

AN XY:

660802

show subpopulations

Gnomad4 AFR exome

AF:

0.0000339

Gnomad4 AMR exome

AF:

0.000103

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000282

Gnomad4 SAS exome

AF:

0.0000141

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000190

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000249

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.18

.;.;T;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Uncertain

0.069

MutationAssessor

Pathogenic

4.7

.;.;H;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.8

.;.;D;.

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

.;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.80, 0.79

MutPred

0.77

.;.;Gain of MoRF binding (P = 0.0021);.;

MVP

0.58

MPC

0.72

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.040

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over