3-57227866-C-T

Position:

• chr3-57227866-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_012096.3(APPL1):​c.-18C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,458,332 control chromosomes in the GnomAD database, including 2,171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (1268 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (903 hom.)
• Consequence: APPL1 NM_012096.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.226

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 3-57227866-C-T is Benign according to our data. Variant chr3-57227866-C-T is described in ClinVar as [Benign]. Clinvar id is 1251769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL1	NM_012096.3	c.-18C>T		5_prime_UTR_variant	1/22	ENST00000288266.8
APPL1	XM_011533583.4	c.-123C>T		5_prime_UTR_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8	c.-18C>T		5_prime_UTR_variant	1/22	1	NM_012096.3	P1

Frequencies

GnomAD3 genomes AF: 0.0705 AC: 10710 AN: 151902 Hom.: 1265 Cov.: 33

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0550

GnomAD3 exomes AF: 0.00930 AC: 854 AN: 91852 Hom.: 68 AF XY: 0.00650 AC XY: 335 AN XY: 51506

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.00658

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000603

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000705

Gnomad OTH exome AF: 0.00659

GnomAD4 exome AF: 0.00661 AC: 8635 AN: 1306322 Hom.: 903 Cov.: 30 AF XY: 0.00580 AC XY: 3740 AN XY: 644428

Gnomad4 AFR exome AF: 0.249

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.00542

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000569

Gnomad4 FIN exome AF: 0.0000286

Gnomad4 NFE exome AF: 0.000420

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0707 AC: 10746 AN: 152010 Hom.: 1268 Cov.: 33 AF XY: 0.0698 AC XY: 5191 AN XY: 74346

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.0289

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0545

Alfa AF: 0.0496 Hom.: 122

Bravo AF: 0.0795

Asia WGS AF: 0.0120 AC: 42 AN: 3412

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs7643644; hg19: chr3-57261894;