Genetic Variant BACE1:p.Asp424His (chr11-117289802-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D424N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

BACE1
NM_012104.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.88

Publications

3 publications found

Variant links:

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 links:

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]

BACE1-AS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BACE1	NM_012104.6	MANE Select	c.1270G>C	p.Asp424His	missense	Exon 9 of 9	NP_036236.1	P56817-1
BACE1	NM_138972.4		c.1195G>C	p.Asp399His	missense	Exon 9 of 9	NP_620428.1	P56817-2
BACE1	NM_138971.4		c.1138G>C	p.Asp380His	missense	Exon 9 of 9	NP_620427.1	P56817-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BACE1	ENST00000313005.11	TSL:1 MANE Select	c.1270G>C	p.Asp424His	missense	Exon 9 of 9	ENSP00000318585.6	P56817-1
BACE1	ENST00000513780.5	TSL:1	c.1195G>C	p.Asp399His	missense	Exon 9 of 9	ENSP00000424536.1	P56817-2
BACE1	ENST00000445823.6	TSL:1	c.1138G>C	p.Asp380His	missense	Exon 9 of 9	ENSP00000403685.2	P56817-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.085

MetaRNN

Uncertain

0.66

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

0.97

PhyloP100

5.9

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.58

Sift

Uncertain

0.019

Sift4G

Uncertain

0.040

Polyphen

0.98

Vest4

0.61

MutPred

0.40

Loss of catalytic residue at D424 (P = 0.0891)

MVP

0.77

MPC

1.8

ClinPred

0.96

GERP RS

5.5

Varity_R

0.84

gMVP

0.81

Mutation Taster

=34/66

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over