3-57238087-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_012096.3(APPL1):c.256T>C(p.Leu86=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,611,706 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (40 hom.)
• Consequence: APPL1 NM_012096.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.982

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 3-57238087-T-C is Benign according to our data. Variant chr3-57238087-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 713805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.982 with no splicing effect.
• BS2: High AC in GnomAd at 722 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL1	NM_012096.3	c.256T>C	p.Leu86=	synonymous_variant	4/22	ENST00000288266.8
APPL1	XM_011533583.4	c.205T>C	p.Leu69=	synonymous_variant	5/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8	c.256T>C	p.Leu86=	synonymous_variant	4/22	1	NM_012096.3	P1

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 722 AN: 152202 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00631

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00572 AC: 1426 AN: 249424 Hom.: 6 AF XY: 0.00558 AC XY: 752 AN XY: 134730

Gnomad AFR exome AF: 0.000741

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00647

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.00784

Gnomad OTH exome AF: 0.00526

GnomAD4 exome AF: 0.00565 AC: 8242 AN: 1459386 Hom.: 40 Cov.: 29 AF XY: 0.00544 AC XY: 3949 AN XY: 725798

Gnomad4 AFR exome AF: 0.000779

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00578

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00149

Gnomad4 FIN exome AF: 0.0143

Gnomad4 NFE exome AF: 0.00612

Gnomad4 OTH exome AF: 0.00524

GnomAD4 genome AF: 0.00474 AC: 722 AN: 152320 Hom.: 2 Cov.: 33 AF XY: 0.00485 AC XY: 361 AN XY: 74480

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00419

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0152

Gnomad4 NFE AF: 0.00631

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00529 Hom.: 2

Bravo AF: 0.00363

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00581

EpiControl AF: 0.00564

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	APPL1: BP4, BP7, BS1, BS2 -

Maturity-onset diabetes of the young type 14 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 29, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 29, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	- -

APPL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2019

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
BayesDel_noAF	Benign	-0.48
Cadd	Benign	9.4
Dann	Benign	0.80

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

Other links and lift over

dbSNP: rs147166062; hg19: chr3-57272115;