3-57238122-C-T

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.285+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00892 in 1,598,026 control chromosomes in the GnomAD database, including 1,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (587 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (474 hom.)
• Consequence: APPL1 NM_012096.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00001799
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.743

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=-0.78).
• BP6: Variant 3-57238122-C-T is Benign according to our data. Variant chr3-57238122-C-T is described in ClinVar as [Benign]. Clinvar id is 1169476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL1	NM_012096.3	c.285+6C>T		splice_donor_region_variant, intron_variant		ENST00000288266.8
APPL1	XM_011533583.4	c.234+6C>T		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8	c.285+6C>T		splice_donor_region_variant, intron_variant		1	NM_012096.3	P1

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 7153 AN: 152034 Hom.: 586 Cov.: 33

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0233

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.0398

GnomAD3 exomes AF: 0.0126 AC: 3059 AN: 243104 Hom.: 199 AF XY: 0.00909 AC XY: 1193 AN XY: 131224

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.00633

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000692

Gnomad OTH exome AF: 0.00605

GnomAD4 exome AF: 0.00490 AC: 7081 AN: 1445874 Hom.: 474 Cov.: 27 AF XY: 0.00426 AC XY: 3064 AN XY: 719066

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.00533

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000204

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000376

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.0472 AC: 7176 AN: 152152 Hom.: 587 Cov.: 33 AF XY: 0.0470 AC XY: 3496 AN XY: 74378

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.0232

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0235 Hom.: 109

Bravo AF: 0.0533

Asia WGS AF: 0.00779 AC: 28 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	Oct 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	12
Dann	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0020
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: rs28578906; hg19: chr3-57272150;