chr11-117293074-G-C

Variant names:

• chr11-117293074-G-C
• rs978679563
• NM_012104.6:c.820C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_012104.6(BACE1):​c.820C>G​(p.Leu274Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BACE1 NM_012104.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.41
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

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.820C>G	p.Leu274Val	missense	Exon 5 of 9	NP_036236.1	P56817-1
	BACE1	NM_138972.4		c.745C>G	p.Leu249Val	missense	Exon 5 of 9	NP_620428.1	P56817-2
	BACE1	NM_138971.4		c.688C>G	p.Leu230Val	missense	Exon 5 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.820C>G	p.Leu274Val	missense	Exon 5 of 9	ENSP00000318585.6	P56817-1
	BACE1	ENST00000513780.5	TSL:1	c.745C>G	p.Leu249Val	missense	Exon 5 of 9	ENSP00000424536.1	P56817-2
	BACE1	ENST00000445823.6	TSL:1	c.688C>G	p.Leu230Val	missense	Exon 5 of 9	ENSP00000403685.2	P56817-3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461740 Hom.: 0 Cov.: 39 AF XY: 0.00000550 AC XY: 4 AN XY: 727168

African (AFR) AF: 0.000179 AC: 6 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111958

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74264

African (AFR) AF: 0.0000967 AC: 4 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000869

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.066	T
Polyphen		0.23	B
Vest4		0.57
MVP		0.28
MPC		1.2
ClinPred		0.76	D
GERP RS		6.1
Varity_R		0.85
gMVP		0.62
Mutation Taster		=25/75	disease causing

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: rs978679563; hg19: chr11-117163790;