8-42167257-G-T

Variant names:

• chr8-42167257-G-T
• NM_006803.4:c.897G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006803.4(AP3M2):​c.897G>T​(p.Gln299His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.82

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.335415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP3M2	NM_006803.4	c.897G>T	p.Gln299His	missense_variant	Exon 7 of 9	ENST00000396926.8	NP_006794.1
AP3M2	NM_001134296.2	c.897G>T	p.Gln299His	missense_variant	Exon 8 of 10		NP_001127768.1
AP3M2	XM_047421275.1	c.552G>T	p.Gln184His	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.897G>T	p.Gln299His	missense_variant	Exon 7 of 9	1	NM_006803.4	ENSP00000380132.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

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 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.897G>T (p.Q299H) alteration is located in exon 8 (coding exon 6) of the AP3M2 gene. This alteration results from a G to T substitution at nucleotide position 897, causing the glutamine (Q) at amino acid position 299 to be replaced by a histidine (H). 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	Uncertain	0.39
BayesDel_addAF	Benign	0.0059	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;T;T
Eigen	Benign	-0.032
Eigen_PC	Benign	0.096
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	.;D;.;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	N;N;N;D
REVEL	Benign	0.24
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.0040	B;B;B;.
Vest4		0.75
MutPred		0.56		Gain of catalytic residue at M301 (P = 0.0355);Gain of catalytic residue at M301 (P = 0.0355);Gain of catalytic residue at M301 (P = 0.0355);.;
MVP		0.30
MPC		0.42
ClinPred		0.71	D
GERP RS		3.4
Varity_R		0.16
gMVP		0.48

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: chr8-42024775;