Genetic Variant NM_130787.3:c.1468C>T (chr19-49800973-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_130787.3(AP2A1):c.1468C>T(p.Pro490Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

AP2A1
NM_130787.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.82

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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
AP2A1	NM_130787.3 link	c.1468C>T	p.Pro490Ser	missense_variant	Exon 12 of 23	ENST00000354293.10	NP_570603.2	O95782-2
AP2A1	NM_014203.3 link	c.1468C>T	p.Pro490Ser	missense_variant	Exon 12 of 24		NP_055018.2	O95782-1
AP2A1	XM_011526556.3 link	c.1519C>T	p.Pro507Ser	missense_variant	Exon 12 of 24		XP_011524858.1
AP2A1	XM_011526557.4 link	c.1519C>T	p.Pro507Ser	missense_variant	Exon 12 of 23		XP_011524859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AP2A1	ENST00000354293.10 link	c.1468C>T	p.Pro490Ser	missense_variant	Exon 12 of 23	1	NM_130787.3	ENSP00000346246.4	O95782-2
AP2A1	ENST00000359032.10 link	c.1468C>T	p.Pro490Ser	missense_variant	Exon 12 of 24	5		ENSP00000351926.4	O95782-1
AP2A1	ENST00000597774.5 link	n.*727C>T		non_coding_transcript_exon_variant	Exon 11 of 22	5		ENSP00000472492.1	M0R2D9
AP2A1	ENST00000597774.5 link	n.*727C>T		3_prime_UTR_variant	Exon 11 of 22	5		ENSP00000472492.1	M0R2D9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449142

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719572

show subpopulations

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:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1468C>T (p.P490S) alteration is located in exon 12 (coding exon 12) of the AP2A1 gene. This alteration results from a C to T substitution at nucleotide position 1468, causing the proline (P) at amino acid position 490 to be replaced by a serine (S). 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

0.51

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.58

D;D

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

L;L

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.2

D;D

REVEL

Benign

0.25

Sift

Benign

0.068

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.92

P;D

Vest4

0.51

MutPred

0.57

Gain of helix (P = 0.132);Gain of helix (P = 0.132);

MVP

0.58

MPC

1.6

ClinPred

0.98

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.74

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over