12-105235461-A-G

Variant names:

• chr12-105235461-A-G
• rs1107756
• NM_018171.5:c.54+498T>C

Variant summary

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

The NM_018171.5(APPL2):​c.54+498T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 152,128 control chromosomes in the GnomAD database, including 8,753 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 0.33 (8749 hom., cov: 32)
  • Exomes 𝑓: 0.25 (4 hom.)
• Consequence: APPL2 NM_018171.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

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]

C12orf75 (HGNC:35164): (chromosome 12 open reading frame 75)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APPL2	NM_018171.5	c.54+498T>C		intron_variant	Intron 1 of 20	ENST00000258530.8	NP_060641.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APPL2	ENST00000258530.8	c.54+498T>C		intron_variant	Intron 1 of 20	1	NM_018171.5	ENSP00000258530.3

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50258 AN: 151946 Hom.: 8741 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.337

GnomAD4 exome AF: 0.250 AC: 16 AN: 64 Hom.: 4 AF XY: 0.406 AC XY: 13 AN XY: 32

Gnomad4 AFR exome AF: 0.100

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.275

GnomAD4 genome AF: 0.331 AC: 50308 AN: 152064 Hom.: 8749 Cov.: 32 AF XY: 0.326 AC XY: 24264 AN XY: 74320

Gnomad4 AFR AF: 0.233

Gnomad4 AMR AF: 0.330

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.347

Gnomad4 SAS AF: 0.241

Gnomad4 FIN AF: 0.348

Gnomad4 NFE AF: 0.391

Gnomad4 OTH AF: 0.342

Alfa AF: 0.349 Hom.: 1559

Bravo AF: 0.331

Asia WGS AF: 0.342 AC: 1189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.7
DANN	Benign	0.71

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: rs1107756; hg19: chr12-105629239;