3-57268465-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_012096.3(APPL1):c.1961A>G(p.Asn654Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,605,176 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: APPL1 NM_012096.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.320

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014890015).
• BP6: Variant 3-57268465-A-G is Benign according to our data. Variant chr3-57268465-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1318138.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL1	NM_012096.3	c.1961A>G	p.Asn654Ser	missense_variant	21/22	ENST00000288266.8
ASB14	NM_001142733.3	c.*1176T>C		3_prime_UTR_variant	11/11	ENST00000487349.6
APPL1	XM_011533583.4	c.1910A>G	p.Asn637Ser	missense_variant	22/23
ASB14	NM_130387.5	c.*1176T>C		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8	c.1961A>G	p.Asn654Ser	missense_variant	21/22	1	NM_012096.3	P1
ASB14	ENST00000487349.6	c.*1176T>C		3_prime_UTR_variant	11/11	1	NM_001142733.3	P1
APPL1	ENST00000650354.1	c.1961A>G	p.Asn654Ser	missense_variant, NMD_transcript_variant	21/24

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000407 AC: 98 AN: 240654 Hom.: 0 AF XY: 0.000444 AC XY: 58 AN XY: 130496

Gnomad AFR exome AF: 0.000383

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000972

Gnomad NFE exome AF: 0.000811

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.00109 AC: 1582 AN: 1452816 Hom.: 2 Cov.: 30 AF XY: 0.00105 AC XY: 762 AN XY: 722788

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.0000696

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.000134

Gnomad4 NFE exome AF: 0.00138

Gnomad4 OTH exome AF: 0.000484

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.000617 AC XY: 46 AN XY: 74506

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000760 Hom.: 0

Bravo AF: 0.000521

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000420 AC: 51

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	APPL1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2020	This variant is associated with the following publications: (PMID: 33408077) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 654 of the APPL1 protein (p.Asn654Ser). This variant is present in population databases (rs144769112, gnomAD 0.08%), 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: 1318138). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	12
Dann	Benign	0.80
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	N;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.78	N
REVEL	Benign	0.038
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.59
MPC		0.14
ClinPred		0.0045	T
GERP RS		0.79
Varity_R		0.012
gMVP		0.026

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs144769112; hg19: chr3-57302493; COSMIC: COSV55702124; COSMIC: COSV55702124;