chr3-57235647-C-T

Variant names:

• chr3-57235647-C-T
• rs765656762
• NM_012096.3:c.136C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_012096.3(APPL1):​c.136C>T​(p.Arg46Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,460,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: APPL1 NM_012096.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.00

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APPL1	NM_012096.3	c.136C>T	p.Arg46Trp	missense_variant	Exon 2 of 22	ENST00000288266.8	NP_036228.1
APPL1	XM_011533583.4	c.85C>T	p.Arg29Trp	missense_variant	Exon 3 of 23		XP_011531885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APPL1	ENST00000288266.8	c.136C>T	p.Arg46Trp	missense_variant	Exon 2 of 22	1	NM_012096.3	ENSP00000288266.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250582 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135438

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1460246 Hom.: 0 Cov.: 29 AF XY: 0.0000165 AC XY: 12 AN XY: 726408

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The APPL1 p.Arg46Trp variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs765656762) and in control databases in 4 of 250582 chromosomes at a frequency of 0.00001596 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 2 of 34292 chromosomes (freq: 0.000058), East Asian in 1 of 18360 chromosomes (freq: 0.000054) and European (non-Finnish) in 1 of 113508 chromosomes (freq: 0.000009), but was not observed in the African, Ashkenazi Jewish, European (Finnish), Other, or South Asian populations. The p.Arg46 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.1	D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;B
Vest4		0.88
MutPred		0.49		Loss of disorder (P = 0.05);Loss of disorder (P = 0.05);.;
MVP		0.82
MPC		0.74
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.62
gMVP		0.64

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: rs765656762; hg19: chr3-57269675;