3-57260057-C-G

Position:

• chr3-57260057-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012096.3(APPL1):​c.1658+38C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,605,404 control chromosomes in the GnomAD database, including 142,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12600 hom., cov: 32)
  • Exomes 𝑓: 0.41 (129545 hom.)
• Consequence: APPL1 NM_012096.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.497

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-57260057-C-G is Benign according to our data. Variant chr3-57260057-C-G is described in ClinVar as [Benign]. Clinvar id is 1257896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL1	NM_012096.3	c.1658+38C>G		intron_variant		ENST00000288266.8
APPL1	XM_011533583.4	c.1607+38C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8	c.1658+38C>G		intron_variant		1	NM_012096.3	P1

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57586 AN: 151880 Hom.: 12579 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.847

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.386

GnomAD3 exomes AF: 0.467 AC: 112797 AN: 241728 Hom.: 29121 AF XY: 0.463 AC XY: 60637 AN XY: 130834

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.624

Gnomad ASJ exome AF: 0.479

Gnomad EAS exome AF: 0.853

Gnomad SAS exome AF: 0.466

Gnomad FIN exome AF: 0.488

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.410 AC: 596146 AN: 1453406 Hom.: 129545 Cov.: 34 AF XY: 0.412 AC XY: 298043 AN XY: 722776

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.607

Gnomad4 ASJ exome AF: 0.475

Gnomad4 EAS exome AF: 0.858

Gnomad4 SAS exome AF: 0.467

Gnomad4 FIN exome AF: 0.484

Gnomad4 NFE exome AF: 0.383

Gnomad4 OTH exome AF: 0.421

GnomAD4 genome AF: 0.379 AC: 57623 AN: 151998 Hom.: 12600 Cov.: 32 AF XY: 0.389 AC XY: 28941 AN XY: 74308

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.528

Gnomad4 ASJ AF: 0.478

Gnomad4 EAS AF: 0.848

Gnomad4 SAS AF: 0.500

Gnomad4 FIN AF: 0.490

Gnomad4 NFE AF: 0.393

Gnomad4 OTH AF: 0.392

Alfa AF: 0.336 Hom.: 1664

Bravo AF: 0.374

Asia WGS AF: 0.643 AC: 2233 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.43
DANN	Benign	0.53

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: rs10510791; hg19: chr3-57294085;