11-117291719-G-C

Variant names:

• chr11-117291719-G-C
• rs542748548
• NM_012104.6:c.935C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012104.6(BACE1):​c.935C>G​(p.Ala312Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,326 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BACE1 NM_012104.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.42

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37719455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BACE1	NM_012104.6	c.935C>G	p.Ala312Gly	missense_variant	Exon 6 of 9	ENST00000313005.11	NP_036236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BACE1	ENST00000313005.11	c.935C>G	p.Ala312Gly	missense_variant	Exon 6 of 9	1	NM_012104.6	ENSP00000318585.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251198 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459326 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.;.;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.38	T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.9	L;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N;.;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.11	T;.;D;T;T;T
Sift4G	Benign	0.32	T;T;T;T;T;T
Polyphen		0.10	B;.;.;P;B;P
Vest4		0.45
MutPred		0.47		Loss of stability (P = 0.039);.;.;.;.;.;
MVP		0.52
MPC		1.3
ClinPred		0.87	D
GERP RS		5.9
Varity_R		0.84
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs542748548; hg19: chr11-117162435;