3-57269656-A-G

Position:

chr3-57269656-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012096.3(APPL1):c.2099A>G(p.Glu700Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,613,446 control chromosomes in the GnomAD database, including 24,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.12 ( 1441 hom., cov: 32)

Exomes 𝑓: 0.17 ( 23236 hom. )

Consequence

APPL1
NM_012096.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.65

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015658736).

BP6

Variant 3-57269656-A-G is Benign according to our data. Variant chr3-57269656-A-G is described in ClinVar as [Benign]. Clinvar id is 1168989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
APPL1	NM_012096.3 linkuse as main transcript	c.2099A>G	p.Glu700Gly	missense_variant	22/22	ENST00000288266.8	NP_036228.1
ASB14	NM_001142733.3 linkuse as main transcript	c.*23-38T>C		intron_variant		ENST00000487349.6	NP_001136205.2
LOC105377102	NR_135535.1 linkuse as main transcript	n.91A>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APPL1	ENST00000288266.8 linkuse as main transcript	c.2099A>G	p.Glu700Gly	missense_variant	22/22	1	NM_012096.3	ENSP00000288266	P1
ASB14	ENST00000487349.6 linkuse as main transcript	c.*23-38T>C		intron_variant		1	NM_001142733.3	ENSP00000419199	P1	A6NK59-3
APPL1	ENST00000650354.1 linkuse as main transcript	c.2099A>G	p.Glu700Gly	missense_variant, NMD_transcript_variant	22/24			ENSP00000498115

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

17989

AN:

152036

Hom.:

1441

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0328

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.117

Gnomad ASJ

AF:

0.0355

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.111

Gnomad FIN

AF:

0.178

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.177

Gnomad OTH

AF:

0.108

GnomAD3 exomes

AF:

0.129

AC:

32481

AN:

251348

Hom.:

2721

AF XY:

0.132

AC XY:

17991

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.0295

Gnomad AMR exome

AF:

0.102

Gnomad ASJ exome

AF:

0.0402

Gnomad EAS exome

AF:

0.000815

Gnomad SAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.178

Gnomad NFE exome

AF:

0.174

Gnomad OTH exome

AF:

0.140

GnomAD4 exome

AF:

0.169

AC:

247627

AN:

1461292

Hom.:

23236

Cov.:

AF XY:

0.168

AC XY:

121800

AN XY:

726954

show subpopulations

Gnomad4 AFR exome

AF:

0.0247

Gnomad4 AMR exome

AF:

0.105

Gnomad4 ASJ exome

AF:

0.0414

Gnomad4 EAS exome

AF:

0.000706

Gnomad4 SAS exome

AF:

0.118

Gnomad4 FIN exome

AF:

0.179

Gnomad4 NFE exome

AF:

0.191

Gnomad4 OTH exome

AF:

0.146

GnomAD4 genome

AF:

0.118

AC:

17984

AN:

152154

Hom.:

1441

Cov.:

AF XY:

0.117

AC XY:

8690

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0327

Gnomad4 AMR

AF:

0.117

Gnomad4 ASJ

AF:

0.0355

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.110

Gnomad4 FIN

AF:

0.178

Gnomad4 NFE

AF:

0.177

Gnomad4 OTH

AF:

0.107

Alfa

AF:

0.156

Hom.:

4755

Bravo

AF:

0.109

TwinsUK

AF:

0.186

AC:

690

ALSPAC

AF:

0.201

AC:

775

ESP6500AA

AF:

0.0433

AC:

191

ESP6500EA

AF:

0.171

AC:

1470

ExAC

AF:

0.130

AC:

15752

Asia WGS

AF:

0.0480

AC:

169

AN:

3478

EpiCase

AF:

0.165

EpiControl

AF:

0.161

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.060

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

0.000013

P;P;P

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

REVEL

Benign

0.14

Sift

Uncertain

0.0070

Sift4G

Benign

0.18

Polyphen

0.46

Vest4

0.17

MPC

0.26

ClinPred

0.052

GERP RS

5.7

Varity_R

0.14

gMVP

0.12

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