rs3751191

chr12-105220677-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018171.5(APPL2):c.154-2952C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 152,226 control chromosomes in the GnomAD database, including 400 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.066 (400 hom., cov: 33)
• Consequence: APPL2 NM_018171.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.105

Genes affected

APPL2 (HGNC:18242): (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2) The protein encoded by this gene is one of two effectors of the small GTPase RAB5A/Rab5, which are involved in a signal transduction pathway. Both effectors contain an N-terminal Bin/Amphiphysin/Rvs (BAR) domain, a central pleckstrin homology (PH) domain, and a C-terminal phosphotyrosine binding (PTB) domain, and they bind the Rab5 through the BAR domain. They are associated with endosomal membranes and can be translocated to the nucleus in response to the EGF stimulus. They interact with the NuRD/MeCP1 complex (nucleosome remodeling and deacetylase /methyl-CpG-binding protein 1 complex) and are required for efficient cell proliferation. A chromosomal aberration t(12;22)(q24.1;q13.3) involving this gene and the PSAP2 gene results in 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL2	NM_018171.5	c.154-2952C>T		intron_variant		ENST00000258530.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL2	ENST00000258530.8	c.154-2952C>T		intron_variant		1	NM_018171.5	P1

Frequencies

GnomAD3 genomes AF: 0.0662 AC: 10068 AN: 152108 Hom.: 399 Cov.: 33

Gnomad AFR AF: 0.0961

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.0654

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.0767

Gnomad FIN AF: 0.0539

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0684

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

GnomAD4 genome AF: 0.0663 AC: 10090 AN: 152226 Hom.: 400 Cov.: 33 AF XY: 0.0667 AC XY: 4966 AN XY: 74430

Gnomad4 AFR AF: 0.0962

Gnomad4 AMR AF: 0.0388

Gnomad4 ASJ AF: 0.0654

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.0769

Gnomad4 FIN AF: 0.0539

Gnomad4 NFE AF: 0.0499

Gnomad4 OTH AF: 0.0747

Alfa AF: 0.0508 Hom.: 231

Bravo AF: 0.0668

Asia WGS AF: 0.123 AC: 429 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
Cadd	Benign	1.1
Dann	Benign	0.25

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: rs3751191; hg19: chr12-105614455;