rs63750847

Positions:

• chr21-25897620-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PM1 PM5 BP4_Strong BP6_Moderate BS2

The NM_000484.4(APP):​c.2017G>A​(p.Ala673Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A673V) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: APP NM_000484.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 2.93

Genes affected

APP (HGNC:620): (amyloid beta precursor protein) This gene encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a number of peptides. Some of these peptides are secreted and can bind to the acetyltransferase complex APBB1/TIP60 to promote transcriptional activation, while others form the protein basis of the amyloid plaques found in the brains of patients with Alzheimer disease. In addition, two of the peptides are antimicrobial peptides, having been shown to have bacteriocidal and antifungal activities. Mutations in this gene have been implicated in autosomal dominant Alzheimer disease and cerebroarterial amyloidosis (cerebral amyloid angiopathy). Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Aug 2014]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000484.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-25897619-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18106.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.015611917).
• BP6: Variant 21-25897620-C-T is Benign according to our data. Variant chr21-25897620-C-T is described in ClinVar as [Benign]. Clinvar id is 37145.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APP	NM_000484.4	c.2017G>A	p.Ala673Thr	missense_variant	16/18	ENST00000346798.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APP	ENST00000346798.8	c.2017G>A	p.Ala673Thr	missense_variant	16/18	1	NM_000484.4

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000446 AC: 112 AN: 251392 Hom.: 0 AF XY: 0.000412 AC XY: 56 AN XY: 135862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000178 AC: 260 AN: 1461750 Hom.: 0 Cov.: 30 AF XY: 0.000166 AC XY: 121 AN XY: 727186

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: 0.00345

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000283 AC: 43 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000469 AC: 57

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alzheimer disease, protection against Benign:1

protective, no assertion criteria provided

literature only

OMIM

Aug 02, 2012

- -

Alzheimer disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

not provided Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.;.;.;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.016	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.095	D
MutationAssessor	Benign	0.46	N;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.65	N;N;N;N;.;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.20	T;T;T;T;.;T;T;T
Sift4G	Benign	0.57	T;T;T;T;T;T;T;T
Polyphen		0.13	B;B;B;B;.;.;B;.
Vest4		0.39
MVP		0.80
MPC		0.41
ClinPred		0.044	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.80

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: rs63750847; hg19: chr21-27269932;