Genetic Variant NM_006803.4:c.415A>G (chr8-42158082-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_006803.4(AP3M2):c.415A>G(p.Ile139Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AP3M2
NM_006803.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.86

Variant links:

Genes affected

AP3M2 (HGNC:570): (adaptor related protein complex 3 subunit mu 2) This gene encodes a subunit of the heterotetrameric adaptor-related protein comlex 3 (AP-3), which belongs to the adaptor complexes medium subunits family. The AP-3 complex plays a role in protein trafficking to lysosomes and specialized organelles. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Aug 2008]

AP3M2 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
AP3M2	NM_006803.4 link	c.415A>G	p.Ile139Val	missense_variant	Exon 3 of 9	ENST00000396926.8	NP_006794.1	P53677-1A0A384NYL6
AP3M2	NM_001134296.2 link	c.415A>G	p.Ile139Val	missense_variant	Exon 4 of 10		NP_001127768.1	P53677-1A0A384NYL6
AP3M2	XM_047421275.1 link	c.70A>G	p.Ile24Val	missense_variant	Exon 2 of 8		XP_047277231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP3M2	ENST00000396926.8 link	c.415A>G	p.Ile139Val	missense_variant	Exon 3 of 9	1	NM_006803.4	ENSP00000380132.3		P53677-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727190

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.415A>G (p.I139V) alteration is located in exon 4 (coding exon 2) of the AP3M2 gene. This alteration results from a A to G substitution at nucleotide position 415, causing the isoleucine (I) at amino acid position 139 to be replaced by a valine (V). 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

0.13

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

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

Eigen

Benign

-0.011

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D;.;D;T;D;D

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.42

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

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.6

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

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.54

N;N;N;N;N;N;N

REVEL

Benign

0.21

Sift

Benign

0.28

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

Sift4G

Benign

0.57

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

Polyphen

0.038

B;B;B;.;.;B;.

Vest4

0.43

MutPred

0.34

Gain of ubiquitination at K135 (P = 0.1204);Gain of ubiquitination at K135 (P = 0.1204);Gain of ubiquitination at K135 (P = 0.1204);.;Gain of ubiquitination at K135 (P = 0.1204);Gain of ubiquitination at K135 (P = 0.1204);.;

MVP

0.67

MPC

0.34

ClinPred

0.91

GERP RS

4.8

Varity_R

0.13

gMVP

0.26

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.

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