19-49795732-C-A

Position:

• chr19-49795732-C-A

Variant summary

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

The NM_130787.3(AP2A1):​c.808C>A​(p.Pro270Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P270L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AP2A1 NM_130787.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

Genes affected

AP2A1 (HGNC:561): (adaptor related protein complex 2 subunit alpha 1) This gene encodes the alpha 1 adaptin subunit of the adaptor protein 2 (AP-2) complex found in clathrin coated vesicles. The AP-2 complex is a heterotetramer consisting of two large adaptins (alpha or beta), a medium adaptin (mu), and a small adaptin (sigma). The complex is part of the protein coat on the cytoplasmic face of coated vesicles which links clathrin to receptors in vesicles. Alternative splicing of this gene results in two transcript variants encoding two different isoforms. A third transcript variant has been described, but its full length nature has not been determined. [provided by RefSeq, Jul 2008]

AP2A1 (HGNC:):

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/exons	MANE	Protein	UniProt
AP2A1	NM_130787.3	c.808C>A	p.Pro270Thr	missense_variant	7/23	ENST00000354293.10	NP_570603.2
AP2A1	NM_014203.3	c.808C>A	p.Pro270Thr	missense_variant	7/24		NP_055018.2
AP2A1	XM_011526556.3	c.859C>A	p.Pro287Thr	missense_variant	7/24		XP_011524858.1
AP2A1	XM_011526557.4	c.859C>A	p.Pro287Thr	missense_variant	7/23		XP_011524859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP2A1	ENST00000354293.10	c.808C>A	p.Pro270Thr	missense_variant	7/23	1	NM_130787.3	ENSP00000346246.4
AP2A1	ENST00000359032.10	c.808C>A	p.Pro270Thr	missense_variant	7/24	5		ENSP00000351926.4
AP2A1	ENST00000597774.5	n.*146C>A		non_coding_transcript_exon_variant	5/22	5		ENSP00000472492.1
AP2A1	ENST00000597774.5	n.*146C>A		3_prime_UTR_variant	5/22	5		ENSP00000472492.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2024

The c.808C>A (p.P270T) alteration is located in exon 7 (coding exon 7) of the AP2A1 gene. This alteration results from a C to A substitution at nucleotide position 808, causing the proline (P) at amino acid position 270 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	0.38
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.20	T;T
Polyphen		0.91	P;D
Vest4		0.61
MutPred		0.39		Gain of phosphorylation at P270 (P = 0.0097);Gain of phosphorylation at P270 (P = 0.0097);
MVP		0.40
MPC		2.0
ClinPred		0.98	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.50

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: chr19-50298989;