chr19-49782067-A-G

Position:

chr19-49782067-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_130787.3(AP2A1):c.257A>G(p.Asn86Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000192 in 1,566,438 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: 𝑓 0.0000066 ( 0 hom., cov: 31)

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: 9.27

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:

AP2A1 (HGNC:):

AP2A1 links:

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ACMG classification

Classification made for transcript

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=0.34599313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2A1	NM_130787.3 linkuse as main transcript	c.257A>G	p.Asn86Ser	missense_variant	3/23	ENST00000354293.10	NP_570603.2	O95782-2
AP2A1	NM_014203.3 linkuse as main transcript	c.257A>G	p.Asn86Ser	missense_variant	3/24		NP_055018.2	O95782-1
AP2A1	XM_011526556.3 linkuse as main transcript	c.308A>G	p.Asn103Ser	missense_variant	3/24		XP_011524858.1
AP2A1	XM_011526557.4 linkuse as main transcript	c.308A>G	p.Asn103Ser	missense_variant	3/23		XP_011524859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AP2A1	ENST00000354293.10 linkuse as main transcript	c.257A>G	p.Asn86Ser	missense_variant	3/23	1	NM_130787.3	ENSP00000346246.4	O95782-2
AP2A1	ENST00000359032.10 linkuse as main transcript	c.257A>G	p.Asn86Ser	missense_variant	3/24	5		ENSP00000351926.4	O95782-1
AP2A1	ENST00000597774.5 linkuse as main transcript	n.157+97A>G		intron_variant		5		ENSP00000472492.1	M0R2D9
AP2A1	ENST00000600199.1 linkuse as main transcript	n.384A>G		non_coding_transcript_exon_variant	3/8	5

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000113

AC:

AN:

176864

Hom.:

AF XY:

0.00

AC XY:

AN XY:

93488

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000386

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000137

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1415560

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699708

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000269

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000268

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

AF:

0.00000663

AC:

AN:

150878

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73642

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000660

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.257A>G (p.N86S) alteration is located in exon 3 (coding exon 3) of the AP2A1 gene. This alteration results from a A to G substitution at nucleotide position 257, causing the asparagine (N) at amino acid position 86 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

Benign

0.17

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

.;T

Eigen

Benign

-0.036

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-4.0

D;D

REVEL

Benign

0.22

Sift

Benign

0.18

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.0

B;B

Vest4

0.66

MutPred

0.44

Loss of stability (P = 0.0299);Loss of stability (P = 0.0299);

MVP

0.51

MPC

0.98

ClinPred

0.65

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over