8-42167274-T-C

Variant names:

• chr8-42167274-T-C
• rs1564119247
• NM_006803.4:c.914T>C

Variant summary

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

The NM_006803.4(AP3M2):​c.914T>C​(p.Ile305Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,892 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: 0.0000014 (0 hom.)
• Consequence: AP3M2 NM_006803.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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 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	c.914T>C	p.Ile305Thr	missense_variant	Exon 7 of 9	ENST00000396926.8	NP_006794.1
AP3M2	NM_001134296.2	c.914T>C	p.Ile305Thr	missense_variant	Exon 8 of 10		NP_001127768.1
AP3M2	XM_047421275.1	c.569T>C	p.Ile190Thr	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.914T>C	p.Ile305Thr	missense_variant	Exon 7 of 9	1	NM_006803.4	ENSP00000380132.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.914T>C (p.I305T) alteration is located in exon 8 (coding exon 6) of the AP3M2 gene. This alteration results from a T to C substitution at nucleotide position 914, causing the isoleucine (I) at amino acid position 305 to be replaced by a threonine (T). 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	0.40
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;.;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M;M;.
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.075	B;B;B;.
Vest4		0.61
MutPred		0.54		Loss of catalytic residue at I305 (P = 0.02);Loss of catalytic residue at I305 (P = 0.02);Loss of catalytic residue at I305 (P = 0.02);.;
MVP		0.61
MPC		0.54
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.36
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

LitVar

Other links and lift over

dbSNP: rs1564119247; hg19: chr8-42024792;