3-57227933-C-G

Variant summary

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

The NM_012096.3(APPL1):c.50C>G(p.Pro17Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: APPL1 NM_012096.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.15

Genes affected

APPL1 (HGNC:24035): (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) The protein encoded by this gene has been shown to be involved in the regulation of cell proliferation, and in the crosstalk between the adiponectin signalling and insulin signalling pathways. The encoded protein binds many other proteins, including RAB5A, DCC, AKT2, PIK3CA, adiponectin receptors, and proteins of the NuRD/MeCP1 complex. This protein is found associated with endosomal membranes, but can be released by EGF and translocated to the nucleus. [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/exons	MANE	UniProt
APPL1	NM_012096.3	c.50C>G	p.Pro17Arg	missense_variant	1/22	ENST00000288266.8
APPL1	XM_011533583.4	c.-56C>G		5_prime_UTR_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8	c.50C>G	p.Pro17Arg	missense_variant	1/22	1	NM_012096.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 25, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on APPL1 protein function. This variant has not been reported in the literature in individuals affected with APPL1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 17 of the APPL1 protein (p.Pro17Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.46		Gain of solvent accessibility (P = 0.0411);Gain of solvent accessibility (P = 0.0411);
MVP		0.85
MPC		0.73
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.96
gMVP		0.67

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-57261961;