NM_012096.3:c.69A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_012096.3(APPL1):c.69A>G(p.Leu23Leu) 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:5

Conservation

PhyloP100: 2.38

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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. GnomAdExome4 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 GnomAdExome4. There are 10271 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High AC in GnomAd4 at 1766 AD,Unknown gene.

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.69A>G	p.Leu23Leu	synonymous	Exon 2 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.69A>G	p.Leu23Leu	synonymous	Exon 2 of 22	ENSP00000288266.3	Q9UKG1
APPL1	ENST00000482800.5	TSL:1	n.164A>G		non_coding_transcript_exon	Exon 2 of 20
APPL1	ENST00000855520.1		c.69A>G	p.Leu23Leu	synonymous	Exon 2 of 23	ENSP00000525579.1

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

GnomAD2 exomes

AF:

0.0142

AC:

3568

AN:

250926

AF XY:

0.0146

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 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

African (AFR)

AF:

0.00231

AC:

AN:

33346

American (AMR)

AF:

0.0140

AC:

624

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.0544

AC:

1417

AN:

26058

East Asian (EAS)

AF:

0.000101

AC:

AN:

39596

South Asian (SAS)

AF:

0.00832

AC:

715

AN:

85904

European-Finnish (FIN)

AF:

0.00710

AC:

379

AN:

53378

Middle Eastern (MID)

AF:

0.0284

AC:

163

AN:

5744

European-Non Finnish (NFE)

AF:

0.0147

AC:

16260

AN:

1105970

Other (OTH)

AF:

0.0162

AC:

973

AN:

60106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

887

1774

2662

3549

4436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

586

1172

1758

2344

2930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0116

AC:

1766

AN:

152320

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

852

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00260

AC:

108

AN:

41566

American (AMR)

AF:

0.0156

AC:

239

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0593

AC:

206

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00857

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0151

AC:

1025

AN:

68024

Other (OTH)

AF:

0.0213

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

182

273

364

455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0156

Hom.:

Bravo

AF:

0.0120

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Maturity-onset diabetes of the young type 14 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

8.0

(source)

DANN

Benign

0.62

PhyloP100

2.4

Mutation Taster

=99/1

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over