8-42167346-C-G

Variant names:

• chr8-42167346-C-G
• NM_006803.4:c.986C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006803.4(AP3M2):​c.986C>G​(p.Thr329Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AP3M2 NM_006803.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15452373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP3M2	NM_006803.4	c.986C>G	p.Thr329Arg	missense_variant	Exon 7 of 9	ENST00000396926.8	NP_006794.1
AP3M2	NM_001134296.2	c.986C>G	p.Thr329Arg	missense_variant	Exon 8 of 10		NP_001127768.1
AP3M2	XM_047421275.1	c.641C>G	p.Thr214Arg	missense_variant	Exon 6 of 8		XP_047277231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP3M2	ENST00000396926.8	c.986C>G	p.Thr329Arg	missense_variant	Exon 7 of 9	1	NM_006803.4	ENSP00000380132.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.986C>G (p.T329R) alteration is located in exon 8 (coding exon 6) of the AP3M2 gene. This alteration results from a C to G substitution at nucleotide position 986, causing the threonine (T) at amino acid position 329 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	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T;T;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.92	.;D;.;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.36	N;N;N;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.010	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.45
MutPred		0.40		Loss of phosphorylation at T329 (P = 0.0409);Loss of phosphorylation at T329 (P = 0.0409);Loss of phosphorylation at T329 (P = 0.0409);.;
MVP		0.14
MPC		0.46
ClinPred		0.22	T
GERP RS		4.2
Varity_R		0.084
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-42024864;