11-130070075-A-G

Variant names:

• chr11-130070075-A-G
• rs776174946
• NM_001142276.2:c.98A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001382542.1(APLP2):​c.-73A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000136 in 1,474,202 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: APLP2 NM_001382542.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.59

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APLP2	NM_001142276.2	c.98A>G	p.Tyr33Cys	missense_variant	Exon 1 of 17	ENST00000338167.10	NP_001135748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APLP2	ENST00000338167.10	c.98A>G	p.Tyr33Cys	missense_variant	Exon 1 of 17	1	NM_001142276.2	ENSP00000345444.5

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151580 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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

GnomAD4 exome AF: 7.56e-7 AC: 1 AN: 1322622 Hom.: 0 Cov.: 30 AF XY: 0.00000153 AC XY: 1 AN XY: 653360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.50e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151580 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74056

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;.;T;.;.
Eigen	Benign	0.056
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.32	.;T;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.3	L;.;L;L;L;L
PROVEAN	Benign	-2.0	.;N;N;N;N;N
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	.;D;T;D;T;D
Sift4G	Pathogenic	0.0	.;D;T;T;T;T
Polyphen		1.0	D;.;D;D;P;D
Vest4		0.65, 0.67, 0.62, 0.60
MutPred		0.44		Loss of catalytic residue at L28 (P = 0.1771);Loss of catalytic residue at L28 (P = 0.1771);Loss of catalytic residue at L28 (P = 0.1771);Loss of catalytic residue at L28 (P = 0.1771);Loss of catalytic residue at L28 (P = 0.1771);Loss of catalytic residue at L28 (P = 0.1771);
MVP		0.82
MPC		0.56
ClinPred		0.86	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs776174946; hg19: chr11-129939970;