3-57227733-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_012096.3(APPL1):c.-151G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 599,518 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (4 hom.)
• Consequence: APPL1 NM_012096.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.296

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-57227733-G-C is Benign according to our data. Variant chr3-57227733-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1318073.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 603 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL1	NM_012096.3	c.-151G>C		5_prime_UTR_variant	1/22	ENST00000288266.8
APPL1	XM_011533583.4	c.-256G>C		5_prime_UTR_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL1	ENST00000288266.8	c.-151G>C		5_prime_UTR_variant	1/22	1	NM_012096.3	P1
APPL1	ENST00000650354.1	c.-151G>C		5_prime_UTR_variant, NMD_transcript_variant	1/24

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 603 AN: 152150 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.00481 AC: 2151 AN: 447260 Hom.: 4 Cov.: 6 AF XY: 0.00470 AC XY: 1047 AN XY: 222804

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000892

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.00520

Gnomad4 OTH exome AF: 0.00322

GnomAD4 genome AF: 0.00396 AC: 603 AN: 152258 Hom.: 5 Cov.: 33 AF XY: 0.00427 AC XY: 318 AN XY: 74454

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.00550

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00224 Hom.: 0

Bravo AF: 0.00300

Asia WGS AF: 0.000290 AC: 1 AN: 3466

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

Oct 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	10
Dann	Benign	0.64

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113307246; hg19: chr3-57261761;