3-57268429-TAGAG-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1 BP6 BS2

The NM_012096.3(APPL1):c.1930_1933del(p.Arg644Ter) variant causes a frameshift change. The variant allele was found at a frequency of 0.000527 in 1,600,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: APPL1 NM_012096.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.85

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]

ASB14 (HGNC:19766): (ankyrin repeat and SOCS box containing 14) The protein encoded by this gene is a member of the ankyrin repeat and SOCS box-containing (ASB) family of proteins. They contain ankyrin repeat sequence and a SOCS box domain. The SOCS box serves to couple suppressor of cytokine signalling (SOCS) proteins and their binding partners with the elongin B and C complex, possibly targeting them for degradation. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 3-57268429-TAGAG-T is Benign according to our data. Variant chr3-57268429-TAGAG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1315697.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High AC in GnomAd at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL1	NM_012096.3	c.1930_1933del	p.Arg644Ter	frameshift_variant	21/22	ENST00000288266.8
ASB14	NM_001142733.3	c.*1208_*1211del		3_prime_UTR_variant	11/11	ENST00000487349.6
APPL1	XM_011533583.4	c.1879_1882del	p.Arg627Ter	frameshift_variant	22/23
ASB14	NM_130387.5	c.*1208_*1211del		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8	c.1930_1933del	p.Arg644Ter	frameshift_variant	21/22	1	NM_012096.3	P1
ASB14	ENST00000487349.6	c.*1208_*1211del		3_prime_UTR_variant	11/11	1	NM_001142733.3	P1
APPL1	ENST00000650354.1	c.1930_1933del	p.Arg644Ter	frameshift_variant, NMD_transcript_variant	21/24

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000721

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000393 AC: 93 AN: 236942 Hom.: 0 AF XY: 0.000382 AC XY: 49 AN XY: 128406

Gnomad AFR exome AF: 0.000262

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.000172

Gnomad SAS exome AF: 0.000234

Gnomad FIN exome AF: 0.000199

Gnomad NFE exome AF: 0.000635

Gnomad OTH exome AF: 0.000510

GnomAD4 exome AF: 0.000539 AC: 780 AN: 1448224 Hom.: 0 AF XY: 0.000519 AC XY: 374 AN XY: 720536

Gnomad4 AFR exome AF: 0.0000908

Gnomad4 AMR exome AF: 0.000207

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.000178

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.000368

Gnomad4 NFE exome AF: 0.000646

Gnomad4 OTH exome AF: 0.000284

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74372

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000721

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.000457

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 27, 2023	This sequence change creates a premature translational stop signal (p.Arg644*) in the APPL1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in APPL1 cause disease. This variant is present in population databases (rs766602418, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with APPL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1315697). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2020	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs757479184; hg19: chr3-57302457;