rs9143

Positions:

• chr12-105173833-A-G

Variant summary

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

The NM_018171.5(APPL2):​c.*481T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 152,456 control chromosomes in the GnomAD database, including 19,304 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 0.50 (19249 hom., cov: 32)
  • Exomes 𝑓: 0.49 (55 hom.)
• Consequence: APPL2 NM_018171.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.826

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=-0.55).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APPL2	NM_018171.5	c.*481T>C		3_prime_UTR_variant	21/21	ENST00000258530.8	NP_060641.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APPL2	ENST00000258530	c.*481T>C		3_prime_UTR_variant	21/21	1	NM_018171.5	ENSP00000258530.3
APPL2	ENST00000547439.5	n.*1761T>C		non_coding_transcript_exon_variant	21/21	1		ENSP00000449410.1
APPL2	ENST00000547439.5	n.*1761T>C		3_prime_UTR_variant	21/21	1		ENSP00000449410.1

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76111 AN: 151942 Hom.: 19255 Cov.: 32

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.527

GnomAD4 exome AF: 0.495 AC: 196 AN: 396 Hom.: 55 Cov.: 0 AF XY: 0.481 AC XY: 126 AN XY: 262

Gnomad4 AMR exome AF: 0.833

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 0.417

Gnomad4 SAS exome AF: 0.438

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.480

Gnomad4 OTH exome AF: 0.700

GnomAD4 genome AF: 0.501 AC: 76130 AN: 152060 Hom.: 19249 Cov.: 32 AF XY: 0.503 AC XY: 37415 AN XY: 74330

Gnomad4 AFR AF: 0.411

Gnomad4 AMR AF: 0.511

Gnomad4 ASJ AF: 0.680

Gnomad4 EAS AF: 0.423

Gnomad4 SAS AF: 0.609

Gnomad4 FIN AF: 0.577

Gnomad4 NFE AF: 0.530

Gnomad4 OTH AF: 0.522

Alfa AF: 0.531 Hom.: 36030

Bravo AF: 0.486

Asia WGS AF: 0.443 AC: 1543 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	11
DANN	Benign	0.86

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: rs9143; hg19: chr12-105567611;