Genetic Variant APPL1:p.Pro2Arg (chr3-57227888-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012096.3(APPL1):c.5C>G(p.Pro2Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000076 in 1,315,392 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

APPL1
NM_012096.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.15

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

maturity-onset diabetes of the young type 14
Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
monogenic diabetes
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

APPL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012096.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APPL1	NM_012096.3	MANE Select	c.5C>G	p.Pro2Arg	missense	Exon 1 of 22	NP_036228.1	Q9UKG1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APPL1	ENST00000288266.8	TSL:1 MANE Select	c.5C>G	p.Pro2Arg	missense	Exon 1 of 22	ENSP00000288266.3	Q9UKG1
APPL1	ENST00000482800.5	TSL:1	n.100C>G		non_coding_transcript_exon	Exon 1 of 20
APPL1	ENST00000855520.1		c.5C>G	p.Pro2Arg	missense	Exon 1 of 23	ENSP00000525579.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.60e-7

AC:

AN:

1315392

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

648908

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26842

American (AMR)

AF:

0.00

AC:

AN:

29978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22800

East Asian (EAS)

AF:

0.00

AC:

AN:

28974

South Asian (SAS)

AF:

0.00

AC:

AN:

72636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3770

European-Non Finnish (NFE)

AF:

9.62e-7

AC:

AN:

1039134

Other (OTH)

AF:

0.00

AC:

AN:

53920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.77

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.0

PhyloP100

4.2

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.15

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0060

Polyphen

0.97

Vest4

0.20

MutPred

0.41

Loss of helix (P = 0.0033)

MVP

0.85

MPC

0.62

ClinPred

0.99

GERP RS

3.7

PromoterAI

-0.016

Neutral

(source)

Varity_R

0.80

gMVP

0.49

Mutation Taster

=62/38

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over