19-49795678-G-T

Variant names:

• chr19-49795678-G-T
• rs200285849
• NM_130787.3:c.754G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_130787.3(AP2A1):​c.754G>T​(p.Val252Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,421,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. V252I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: AP2A1 NM_130787.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.91
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130787.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP2A1	NM_130787.3	MANE Select	c.754G>T	p.Val252Phe	missense	Exon 7 of 23	NP_570603.2
	AP2A1	NM_014203.3		c.754G>T	p.Val252Phe	missense	Exon 7 of 24	NP_055018.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP2A1	ENST00000354293.10	TSL:1 MANE Select	c.754G>T	p.Val252Phe	missense	Exon 7 of 23	ENSP00000346246.4	O95782-2
	AP2A1	ENST00000359032.10	TSL:5	c.754G>T	p.Val252Phe	missense	Exon 7 of 24	ENSP00000351926.4	O95782-1
	AP2A1	ENST00000597774.5	TSL:5	n.*92G>T		non_coding_transcript_exon	Exon 5 of 22	ENSP00000472492.1	M0R2D9

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1421974 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 703774

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32432

American (AMR) AF: 0.00 AC: 0 AN: 38878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25388

East Asian (EAS) AF: 0.00 AC: 0 AN: 37588

South Asian (SAS) AF: 0.00 AC: 0 AN: 80920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092334

Other (OTH) AF: 0.0000169 AC: 1 AN: 59020

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.68		Loss of phosphorylation at Y249 (P = 0.1047)
MVP		0.68
MPC		2.7
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.81
gMVP		0.88
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200285849; hg19: chr19-50298935;