11-130120743-A-T

Variant names:

• chr11-130120743-A-T
• rs368746535
• NM_001142276.2:c.441A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001142276.2(APLP2):​c.441A>T​(p.Glu147Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: APLP2 NM_001142276.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.906
• Publications: 1 publications found

Genes affected

APLP2 (HGNC:598): (amyloid beta precursor like protein 2) This gene encodes amyloid precursor- like protein 2 (APLP2), which is a member of the APP (amyloid precursor protein) family including APP, APLP1 and APLP2. This protein is ubiquitously expressed. It contains heparin-, copper- and zinc- binding domains at the N-terminus, BPTI/Kunitz inhibitor and E2 domains in the middle region, and transmembrane and intracellular domains at the C-terminus. This protein interacts with major histocompatibility complex (MHC) class I molecules. The synergy of this protein and the APP is required to mediate neuromuscular transmission, spatial learning and synaptic plasticity. This protein has been implicated in the pathogenesis of Alzheimer's disease. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08131176).
• BS2: High AC in GnomAd4 at 28 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142276.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APLP2	NM_001142276.2	MANE Select	c.441A>T	p.Glu147Asp	missense	Exon 4 of 17	NP_001135748.1	Q06481-3
	APLP2	NM_001642.3		c.441A>T	p.Glu147Asp	missense	Exon 4 of 18	NP_001633.1	Q06481-1
	APLP2	NM_001243299.2		c.471A>T	p.Glu157Asp	missense	Exon 4 of 17	NP_001230228.1	Q06481-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APLP2	ENST00000338167.10	TSL:1 MANE Select	c.441A>T	p.Glu147Asp	missense	Exon 4 of 17	ENSP00000345444.5	Q06481-3
	APLP2	ENST00000263574.9	TSL:1	c.441A>T	p.Glu147Asp	missense	Exon 4 of 18	ENSP00000263574.5	Q06481-1
	APLP2	ENST00000528499.5	TSL:1	c.441A>T	p.Glu147Asp	missense	Exon 4 of 16	ENSP00000435914.1	Q06481-4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251294 AF XY: 0.0000442

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461696 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727158

African (AFR) AF: 0.00102 AC: 34 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111862

Other (OTH) AF: 0.0000497 AC: 3 AN: 60378

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74352

African (AFR) AF: 0.000676 AC: 28 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000254 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.045	N
PhyloP100		0.91
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.84	N
REVEL	Benign	0.26
Sift	Benign	0.79	T
Sift4G	Benign	0.53	T
Polyphen		0.024	B
Vest4		0.35
MutPred		0.56		Gain of ubiquitination at K148 (P = 0.0898)
MVP		0.78
MPC		0.13
ClinPred		0.021	T
GERP RS		-0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.066
gMVP		0.40
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs368746535; hg19: chr11-129990638;