rs535219476

Variant names:

• chr11-117289802-C-G
• rs535219476
• NM_012104.6:c.1270G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-117289802-C-G
• chr11-117289802-C-T

Variant summary

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

The NM_012104.6(BACE1):​c.1270G>C​(p.Asp424His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BACE1 NM_012104.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.88

Genes affected

BACE1 (HGNC:933): (beta-secretase 1) This gene encodes a member of the peptidase A1 family of aspartic proteases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protease. This transmembrane protease catalyzes the first step in the formation of amyloid beta peptide from amyloid precursor protein. Amyloid beta peptides are the main constituent of amyloid beta plaques, which accumulate in the brains of human Alzheimer's disease patients. [provided by RefSeq, Nov 2015]

BACE1-AS (HGNC:37125): (BACE1 antisense RNA) This gene encodes an unspliced long non-coding RNA transcribed from the opposite strand to BACE1. The encoded transcript is thought to form an RNA duplex with BACE1 mRNA thereby regulating its expression and is also thought to promote post-transcriptional feed-forward regulation of BACE1. This may lead to increased levels of beta amyloid and increased senile plaque deposition, and therefore may play a role in the pathophysiology of Alzheimer's disease. [provided by RefSeq, Jan 2015]

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
BACE1	NM_012104.6	c.1270G>C	p.Asp424His	missense_variant	Exon 9 of 9	ENST00000313005.11	NP_036236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BACE1	ENST00000313005.11	c.1270G>C	p.Asp424His	missense_variant	Exon 9 of 9	1	NM_012104.6	ENSP00000318585.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;T;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Benign	0.085	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.97	L;.;.;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.9	D;.;D;D;D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.019	D;.;D;D;D;D;D
Sift4G	Uncertain	0.040	D;T;D;T;D;D;D
Polyphen		0.98	D;.;.;.;D;D;D
Vest4		0.61
MutPred		0.40		Loss of catalytic residue at D424 (P = 0.0891);.;.;.;.;.;.;
MVP		0.77
MPC		1.8
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.84
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs535219476; hg19: chr11-117160518;