19-49799444-C-G

Position:

• chr19-49799444-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_130787.3(AP2A1):​c.1083C>G​(p.Phe361Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,459,616 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: AP2A1 NM_130787.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91

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]

LOC124904742 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2A1	NM_130787.3	c.1083C>G	p.Phe361Leu	missense_variant	9/23	ENST00000354293.10	NP_570603.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP2A1	ENST00000354293.10	c.1083C>G	p.Phe361Leu	missense_variant	9/23	1	NM_130787.3	ENSP00000346246.4
AP2A1	ENST00000359032.10	c.1083C>G	p.Phe361Leu	missense_variant	9/24	5		ENSP00000351926.4
AP2A1	ENST00000597774.5	n.*421C>G		non_coding_transcript_exon_variant	7/22	5		ENSP00000472492.1
AP2A1	ENST00000597774.5	n.*421C>G		3_prime_UTR_variant	7/22	5		ENSP00000472492.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1459616 Hom.: 0 Cov.: 32 AF XY: 0.0000262 AC XY: 19 AN XY: 726028

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

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: 0.0000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000113

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

Sep 09, 2024

The c.1083C>G (p.F361L) alteration is located in exon 9 (coding exon 9) of the AP2A1 gene. This alteration results from a C to G substitution at nucleotide position 1083, causing the phenylalanine (F) at amino acid position 361 to be replaced by a leucine (L). 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	Pathogenic	1.0
BayesDel_addAF	Benign	0.0090	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.3	D;D
REVEL	Benign	0.28
Sift	Benign	0.65	T;T
Sift4G	Benign	0.65	T;T
Polyphen		1.0	D;D
Vest4		0.62
MutPred		0.45		Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.65
MPC		1.4
ClinPred		0.83	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.41
gMVP		0.68

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: rs920483294; hg19: chr19-50302701;