12-105235461-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018171.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APPL2	NM_018171.5	MANE Select	c.54+498T>C		intron	N/A	NP_060641.2
	APPL2	NM_001251904.2		c.54+498T>C		intron	N/A	NP_001238833.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APPL2	ENST00000258530.8	TSL:1 MANE Select	c.54+498T>C		intron	N/A	ENSP00000258530.3
	APPL2	ENST00000547439.5	TSL:1	n.54+498T>C		intron	N/A	ENSP00000449410.1
	APPL2	ENST00000551662.5	TSL:2	c.54+498T>C		intron	N/A	ENSP00000446917.1

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

African (AFR) AF: 0.100 AC: 1 AN: 10

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.275 AC: 11 AN: 40

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.233 AC: 9662 AN: 41478

American (AMR) AF: 0.330 AC: 5047 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1033 AN: 3470

East Asian (EAS) AF: 0.347 AC: 1790 AN: 5162

South Asian (SAS) AF: 0.241 AC: 1163 AN: 4816

European-Finnish (FIN) AF: 0.348 AC: 3672 AN: 10556

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26615 AN: 67984

Other (OTH) AF: 0.342 AC: 721 AN: 2108

Alfa AF: 0.346 Hom.: 1583

Bravo AF: 0.331

Asia WGS AF: 0.342 AC: 1189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.7
DANN	Benign	0.71
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1107756; hg19: chr12-105629239;