chr3-57268429-TAGAG-T

Position:

chr3-57268429-TAGAG-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1BP6BS2

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.85

Variant links:

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]

APPL1 links:

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]

ASB14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
APPL1	NM_012096.3 linkuse as main transcript	c.1930_1933del	p.Arg644Ter	frameshift_variant	21/22	ENST00000288266.8	NP_036228.1
ASB14	NM_001142733.3 linkuse as main transcript	c.1208_1211del		3_prime_UTR_variant	11/11	ENST00000487349.6	NP_001136205.2
APPL1	XM_011533583.4 linkuse as main transcript	c.1879_1882del	p.Arg627Ter	frameshift_variant	22/23		XP_011531885.1
ASB14	NM_130387.5 linkuse as main transcript	c.1208_1211del		3_prime_UTR_variant	4/4		NP_569058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APPL1	ENST00000288266.8 linkuse as main transcript	c.1930_1933del	p.Arg644Ter	frameshift_variant	21/22	1	NM_012096.3	ENSP00000288266	P1
ASB14	ENST00000487349.6 linkuse as main transcript	c.1208_1211del		3_prime_UTR_variant	11/11	1	NM_001142733.3	ENSP00000419199	P1	A6NK59-3
APPL1	ENST00000650354.1 linkuse as main transcript	c.1930_1933del	p.Arg644Ter	frameshift_variant, NMD_transcript_variant	21/24			ENSP00000498115

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

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:

AN:

236942

Hom.:

AF XY:

0.000382

AC XY:

AN XY:

128406

show subpopulations

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.:

AF XY:

0.000519

AC XY:

374

AN XY:

720536

show subpopulations

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:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74372

show subpopulations

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.:

Bravo

AF:

0.000457

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over