Variant chr3-57235580-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_012096.3(APPL1):c.69A>G(p.Leu23=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,607,080 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 30 hom., cov: 32)

Exomes 𝑓: 0.014 ( 183 hom. )

Consequence

APPL1
NM_012096.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.38

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 3-57235580-A-G is Benign according to our data. Variant chr3-57235580-A-G is described in ClinVar as [Benign]. Clinvar id is 1170466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.38 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0142 (20612/1454760) while in subpopulation MID AF= 0.0284 (163/5744). AF 95% confidence interval is 0.0248. There are 183 homozygotes in gnomad4_exome. There are 10271 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1766 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL1	NM_012096.3 linkuse as main transcript	c.69A>G	p.Leu23=	synonymous_variant	2/22	ENST00000288266.8
APPL1	XM_011533583.4 linkuse as main transcript	c.18A>G	p.Leu6=	synonymous_variant	3/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8 linkuse as main transcript	c.69A>G	p.Leu23=	synonymous_variant	2/22	1	NM_012096.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1767

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00261

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0156

Gnomad ASJ

AF:

0.0593

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00828

Gnomad FIN

AF:

0.00857

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.0215

GnomAD3 exomes

AF:

0.0142

AC:

3568

AN:

250926

Hom.:

AF XY:

0.0146

AC XY:

1975

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.0140

Gnomad ASJ exome

AF:

0.0554

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00816

Gnomad FIN exome

AF:

0.00688

Gnomad NFE exome

AF:

0.0173

Gnomad OTH exome

AF:

0.0232

GnomAD4 exome

AF:

0.0142

AC:

20612

AN:

1454760

Hom.:

183

Cov.:

AF XY:

0.0142

AC XY:

10271

AN XY:

724132

show subpopulations

Gnomad4 AFR exome

AF:

0.00231

Gnomad4 AMR exome

AF:

0.0140

Gnomad4 ASJ exome

AF:

0.0544

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00832

Gnomad4 FIN exome

AF:

0.00710

Gnomad4 NFE exome

AF:

0.0147

Gnomad4 OTH exome

AF:

0.0162

GnomAD4 genome

AF:

0.0116

AC:

1766

AN:

152320

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

852

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00260

Gnomad4 AMR

AF:

0.0156

Gnomad4 ASJ

AF:

0.0593

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00829

Gnomad4 FIN

AF:

0.00857

Gnomad4 NFE

AF:

0.0151

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.0182

Hom.:

Bravo

AF:

0.0120

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2019	- -

Maturity-onset diabetes of the young type 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

8.0

DANN

Benign

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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