rs535860

Variant names:

• chr11-117289162-A-T
• rs535860
• NM_012104.6:c.*404T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_012104.6(BACE1):​c.*404T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 197,860 control chromosomes in the GnomAD database, including 1,428 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 0.12 (1110 hom., cov: 32)
  • Exomes 𝑓: 0.11 (318 hom.)
• Consequence: BACE1 NM_012104.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.34

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BACE1	NM_012104.6	c.*404T>A		3_prime_UTR_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	c.*404T>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_012104.6	ENSP00000318585.6

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18506 AN: 152060 Hom.: 1106 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0869

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.114

GnomAD4 exome AF: 0.109 AC: 4966 AN: 45682 Hom.: 318 Cov.: 0 AF XY: 0.109 AC XY: 2556 AN XY: 23478

Gnomad4 AFR exome AF: 0.118 AC: 292 AN: 2474

Gnomad4 AMR exome AF: 0.123 AC: 483 AN: 3922

Gnomad4 ASJ exome AF: 0.152 AC: 171 AN: 1122

Gnomad4 EAS exome AF: 0.0908 AC: 357 AN: 3932

Gnomad4 SAS exome AF: 0.106 AC: 449 AN: 4238

Gnomad4 FIN exome AF: 0.129 AC: 218 AN: 1684

Gnomad4 NFE exome AF: 0.105 AC: 2733 AN: 25934

Gnomad4 Remaining exome AF: 0.109 AC: 243 AN: 2236

GnomAD4 genome AF: 0.122 AC: 18520 AN: 152178 Hom.: 1110 Cov.: 32 AF XY: 0.122 AC XY: 9085 AN XY: 74388

Gnomad4 AFR AF: 0.122 AC: 0.121724 AN: 0.121724

Gnomad4 AMR AF: 0.115 AC: 0.115239 AN: 0.115239

Gnomad4 ASJ AF: 0.163 AC: 0.163018 AN: 0.163018

Gnomad4 EAS AF: 0.0869 AC: 0.0869061 AN: 0.0869061

Gnomad4 SAS AF: 0.111 AC: 0.110742 AN: 0.110742

Gnomad4 FIN AF: 0.145 AC: 0.145377 AN: 0.145377

Gnomad4 NFE AF: 0.121 AC: 0.121157 AN: 0.121157

Gnomad4 OTH AF: 0.116 AC: 0.11553 AN: 0.11553

Alfa AF: 0.121 Hom.: 147

Bravo AF: 0.121

Asia WGS AF: 0.0890 AC: 308 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.80
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

Publications

LitVar

Other links and lift over

dbSNP: rs535860; hg19: chr11-117159878; COSMIC: COSV56118969; COSMIC: COSV56118969;