3-57237538-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_012096.3(APPL1):c.200A>G(p.Glu67Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000383 in 1,598,782 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

APPL1
NM_012096.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.72

Variant links:

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]

APPL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008472085).

BP6

Variant 3-57237538-A-G is Benign according to our data. Variant chr3-57237538-A-G is described in ClinVar as [Benign]. Clinvar id is 1336573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd at 296 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL1	NM_012096.3 linkuse as main transcript	c.200A>G	p.Glu67Gly	missense_variant	3/22	ENST00000288266.8
APPL1	XM_011533583.4 linkuse as main transcript	c.149A>G	p.Glu50Gly	missense_variant	4/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8 linkuse as main transcript	c.200A>G	p.Glu67Gly	missense_variant	3/22	1	NM_012096.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

296

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00680

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000541

AC:

128

AN:

236630

Hom.:

AF XY:

0.000336

AC XY:

AN XY:

128076

show subpopulations

Gnomad AFR exome

AF:

0.00806

Gnomad AMR exome

AF:

0.000212

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000709

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.000219

AC:

317

AN:

1446460

Hom.:

Cov.:

AF XY:

0.000170

AC XY:

122

AN XY:

718950

show subpopulations

Gnomad4 AFR exome

AF:

0.00770

Gnomad4 AMR exome

AF:

0.000252

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000602

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000136

Gnomad4 OTH exome

AF:

0.000519

GnomAD4 genome

AF:

0.00194

AC:

296

AN:

152322

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00680

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000167

Hom.:

Bravo

AF:

0.00249

ESP6500AA

AF:

0.00594

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000743

AC:

Asia WGS

AF:

0.000580

AC:

AN:

3462

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 14, 2019

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

APPL1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 06, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.82

T;T;T

MetaRNN

Benign

0.0085

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;.;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.3

N;D;D

REVEL

Benign

0.24

Sift

Benign

0.088

T;T;T

Sift4G

Uncertain

0.051

T;D;D

Polyphen

0.0020

B;.;P

Vest4

0.40

MVP

0.68

MPC

0.22

ClinPred

0.023

GERP RS

5.9

Varity_R

0.25

gMVP

0.46

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

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