chr19-49799681-T-C

Variant names:

• chr19-49799681-T-C
• rs1027601299
• NM_130787.3:c.1187T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_130787.3(AP2A1):​c.1187T>C​(p.Met396Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,460,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: AP2A1 NM_130787.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95

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 -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP2A1	NM_130787.3	c.1187T>C	p.Met396Thr	missense_variant	Exon 10 of 23	ENST00000354293.10	NP_570603.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP2A1	ENST00000354293.10	c.1187T>C	p.Met396Thr	missense_variant	Exon 10 of 23	1	NM_130787.3	ENSP00000346246.4
AP2A1	ENST00000359032.10	c.1187T>C	p.Met396Thr	missense_variant	Exon 10 of 24	5		ENSP00000351926.4
AP2A1	ENST00000597774.5	n.*525T>C		non_coding_transcript_exon_variant	Exon 8 of 22	5		ENSP00000472492.1
AP2A1	ENST00000597774.5	n.*525T>C		3_prime_UTR_variant	Exon 8 of 22	5		ENSP00000472492.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460670 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726660

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1187T>C (p.M396T) alteration is located in exon 10 (coding exon 10) of the AP2A1 gene. This alteration results from a T to C substitution at nucleotide position 1187, causing the methionine (M) at amino acid position 396 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.3	M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.27	B;B
Vest4		0.98
MutPred		0.73		Loss of catalytic residue at M396 (P = 0.004);Loss of catalytic residue at M396 (P = 0.004);
MVP		0.85
MPC		2.5
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.84
gMVP		0.97

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: rs1027601299; hg19: chr19-50302938;