3-57269668-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_012096.3(APPL1):c.2111A>G(p.Lys704Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

APPL1
NM_012096.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 6.93

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:

ASB14 (HGNC:19766): (ankyrin repeat and SOCS box containing 14) The protein encoded by this gene is a member of the ankyrin repeat and SOCS box-containing (ASB) family of proteins. They contain ankyrin repeat sequence and a SOCS box domain. The SOCS box serves to couple suppressor of cytokine signalling (SOCS) proteins and their binding partners with the elongin B and C complex, possibly targeting them for degradation. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Dec 2008]

ASB14 links:

LOC105377102 (HGNC:):

LOC105377102 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.117500395).

BP6

Variant 3-57269668-A-G is Benign according to our data. Variant chr3-57269668-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1923374.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APPL1	NM_012096.3 link	c.2111A>G	p.Lys704Arg	missense_variant	Exon 22 of 22	ENST00000288266.8	NP_036228.1	Q9UKG1
ASB14	NM_001142733.3 link	c.*23-50T>C		intron_variant	Intron 10 of 10	ENST00000487349.6	NP_001136205.2	A6NK59-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APPL1	ENST00000288266.8 link	c.2111A>G	p.Lys704Arg	missense_variant	Exon 22 of 22	1	NM_012096.3	ENSP00000288266.3	Q9UKG1
ASB14	ENST00000487349.6 link	c.*23-50T>C		intron_variant	Intron 10 of 10	1	NM_001142733.3	ENSP00000419199.1	A6NK59-3
ASB14	ENST00000389601.3 link	c.*23-50T>C		intron_variant	Intron 11 of 11	5			A6NK59-1
APPL1	ENST00000650354.1 link	n.2111A>G		non_coding_transcript_exon_variant	Exon 22 of 24			ENSP00000498115.1	Q9UKG1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251272

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

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:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 704 of the APPL1 protein (p.Lys704Arg). This variant is present in population databases (rs142166154, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with APPL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1923374). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

not specified

Benign:1

Feb 07, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.043

Eigen

Benign

0.024

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.0068

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.41

REVEL

Benign

0.12

Sift

Benign

0.094

Sift4G

Benign

0.21

Polyphen

0.0020

Vest4

0.34

MVP

0.69

MPC

0.15

ClinPred

0.14

GERP RS

5.7

Varity_R

0.19

gMVP

0.036

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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