19-16206390-C-A

Variant names:

• chr19-16206390-C-A
• NM_032493.4:c.249C>A

Variant summary

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

The NM_032493.4(AP1M1):​c.249C>A​(p.Phe83Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AP1M1 NM_032493.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.876

Genes affected

AP1M1 (HGNC:13667): (adaptor related protein complex 1 subunit mu 1) The protein encoded by this gene is the medium chain of the trans-Golgi network clathrin-associated protein complex AP-1. The other components of this complex are beta-prime-adaptin, gamma-adaptin, and the small chain AP1S1. This complex is located at the Golgi vesicle and links clathrin to receptors in coated vesicles. These vesicles are involved in endocytosis and Golgi processing. Alternatively spliced transcript variants encoding distinct protein isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

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
AP1M1	NM_032493.4	c.249C>A	p.Phe83Leu	missense_variant	Exon 3 of 12	ENST00000291439.8	NP_115882.1
AP1M1	NM_001130524.2	c.249C>A	p.Phe83Leu	missense_variant	Exon 3 of 13		NP_001123996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP1M1	ENST00000291439.8	c.249C>A	p.Phe83Leu	missense_variant	Exon 3 of 12	1	NM_032493.4	ENSP00000291439.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.249C>A (p.F83L) alteration is located in exon 3 (coding exon 3) of the AP1M1 gene. This alteration results from a C to A substitution at nucleotide position 249, causing the phenylalanine (F) at amino acid position 83 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	0.98
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.;.;T;.;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.2	M;.;.;M;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.5	D;.;D;D;.;.;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.011	D;.;D;D;.;.;.;.
Sift4G	Uncertain	0.017	D;T;D;D;D;D;D;T
Polyphen		0.029	B;.;B;.;.;.;.;.
Vest4		0.92
MutPred		0.65		Loss of methylation at K86 (P = 0.0856);Loss of methylation at K86 (P = 0.0856);Loss of methylation at K86 (P = 0.0856);Loss of methylation at K86 (P = 0.0856);.;.;.;.;
MVP		0.81
MPC		1.5
ClinPred		0.97	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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.

Other links and lift over

hg19: chr19-16317201;