3-57235580-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.38

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 -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 GnomAd at 1767 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8	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.: 30 Cov.: 32

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.: 43 AF XY: 0.0146 AC XY: 1975 AN XY: 135622

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.: 28 AF XY: 0.0142 AC XY: 10271 AN XY: 724132

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.: 30 Cov.: 32 AF XY: 0.0114 AC XY: 852 AN XY: 74490

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.: 20

Bravo AF: 0.0120

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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

Other links and lift over

dbSNP: rs11544592; hg19: chr3-57269608;