11-117289712-T-G

Variant names:

• chr11-117289712-T-G
• rs1469726367
• NM_012104.6:c.1360A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012104.6(BACE1):​c.1360A>C​(p.Thr454Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T454A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BACE1 NM_012104.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• Publications: 1 publications found

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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37760356).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012104.6. 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
	BACE1	NM_012104.6	MANE Select	c.1360A>C	p.Thr454Pro	missense	Exon 9 of 9	NP_036236.1	P56817-1
	BACE1	NM_138972.4		c.1285A>C	p.Thr429Pro	missense	Exon 9 of 9	NP_620428.1	P56817-2
	BACE1	NM_138971.4		c.1228A>C	p.Thr410Pro	missense	Exon 9 of 9	NP_620427.1	P56817-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BACE1	ENST00000313005.11	TSL:1 MANE Select	c.1360A>C	p.Thr454Pro	missense	Exon 9 of 9	ENSP00000318585.6	P56817-1
	BACE1	ENST00000513780.5	TSL:1	c.1285A>C	p.Thr429Pro	missense	Exon 9 of 9	ENSP00000424536.1	P56817-2
	BACE1	ENST00000445823.6	TSL:1	c.1228A>C	p.Thr410Pro	missense	Exon 9 of 9	ENSP00000403685.2	P56817-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.040
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.81	L
PhyloP100		5.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.38
Sift	Benign	0.20	T
Sift4G	Benign	0.13	T
Polyphen		0.0040	B
Vest4		0.55
MutPred		0.31		Loss of catalytic residue at T454 (P = 0.0588)
MVP		0.89
MPC		1.7
ClinPred		0.71	D
GERP RS		5.7
Varity_R		0.37
gMVP		0.93
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

dbSNP: rs1469726367; hg19: chr11-117160428;