3-57235300-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012096.3(APPL1):c.55-266G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 152,070 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.024 (66 hom., cov: 32)
• Consequence: APPL1 NM_012096.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.228

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-57235300-G-C is Benign according to our data. Variant chr3-57235300-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1318328.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0238 (3622/152070) while in subpopulation SAS AF= 0.0357 (172/4814). AF 95% confidence interval is 0.0323. There are 66 homozygotes in gnomad4. There are 1726 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3621 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL1	NM_012096.3	c.55-266G>C		intron_variant		ENST00000288266.8
APPL1	XM_011533583.4	c.4-266G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8	c.55-266G>C		intron_variant		1	NM_012096.3	P1

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3621 AN: 151954 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.00503

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0351

Gnomad FIN AF: 0.0248

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0325

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0238 AC: 3622 AN: 152070 Hom.: 66 Cov.: 32 AF XY: 0.0232 AC XY: 1726 AN XY: 74314

Gnomad4 AFR AF: 0.00501

Gnomad4 AMR AF: 0.0339

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0357

Gnomad4 FIN AF: 0.0248

Gnomad4 NFE AF: 0.0335

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0137 Hom.: 3

Bravo AF: 0.0238

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	7.1
Dann	Benign	0.40

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: rs79525643; hg19: chr3-57269328;