3-57229366-G-C

Variant names:

• chr3-57229366-G-C
• rs4640525
• NM_012096.3:c.54+1429G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012096.3(APPL1):​c.54+1429G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 151,770 control chromosomes in the GnomAD database, including 12,661 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (12661 hom., cov: 31)
• Consequence: APPL1 NM_012096.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.280
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

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.54+1429G>C		intron	N/A	NP_036228.1	Q9UKG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APPL1	ENST00000288266.8	TSL:1 MANE Select	c.54+1429G>C		intron	N/A	ENSP00000288266.3	Q9UKG1
	APPL1	ENST00000482800.5	TSL:1	n.149+1429G>C		intron	N/A
	APPL1	ENST00000855520.1		c.54+1429G>C		intron	N/A	ENSP00000525579.1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56444 AN: 151650 Hom.: 12645 Cov.: 31

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.921

Gnomad SAS AF: 0.503

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.391

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.374

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.372 AC: 56475 AN: 151770 Hom.: 12661 Cov.: 31 AF XY: 0.383 AC XY: 28426 AN XY: 74132

African (AFR) AF: 0.155 AC: 6420 AN: 41398

American (AMR) AF: 0.516 AC: 7854 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1628 AN: 3464

East Asian (EAS) AF: 0.921 AC: 4769 AN: 5178

South Asian (SAS) AF: 0.504 AC: 2426 AN: 4810

European-Finnish (FIN) AF: 0.492 AC: 5157 AN: 10474

Middle Eastern (MID) AF: 0.387 AC: 113 AN: 292

European-Non Finnish (NFE) AF: 0.394 AC: 26784 AN: 67910

Other (OTH) AF: 0.381 AC: 803 AN: 2108

Alfa AF: 0.383 Hom.: 1530

Bravo AF: 0.365

Asia WGS AF: 0.671 AC: 2329 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.3
DANN	Benign	0.55
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4640525; hg19: chr3-57263394;