14-73136992-G-C

Variant names:

• chr14-73136992-G-C
• rs1800844
• ENST00000394164.5:c.-367G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000394164.5(PSEN1):​c.-367G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 155,432 control chromosomes in the GnomAD database, including 2,930 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 0.17 (2845 hom., cov: 32)
  • Exomes 𝑓: 0.21 (85 hom.)
• Consequence: PSEN1 ENST00000394164.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.484
• Publications: 10 publications found

Genes affected

PSEN1 (HGNC:9508): (presenilin 1) Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or in the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene, the full-length nature of only some have been determined. [provided by RefSeq, Aug 2008]

PSEN1 Gene-Disease associations (from GenCC):

• Alzheimer disease 3

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Pick disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• semantic dementia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• behavioral variant of frontotemporal dementia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset autosomal dominant Alzheimer disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acne inversa, familial, 3

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1U

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000394164.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN1	NM_000021.4	MANE Select	c.-136+409G>C		intron	N/A	NP_000012.1
	PSEN1	NM_007318.3		c.-136+409G>C		intron	N/A	NP_015557.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN1	ENST00000394164.5	TSL:1	c.-367G>C		5_prime_UTR	Exon 1 of 12	ENSP00000377719.1
	PSEN1	ENST00000324501.10	TSL:1 MANE Select	c.-136+409G>C		intron	N/A	ENSP00000326366.5
	PSEN1	ENST00000357710.8	TSL:1	c.-136+409G>C		intron	N/A	ENSP00000350342.4

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25498 AN: 152064 Hom.: 2847 Cov.: 32

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.196

GnomAD4 exome AF: 0.211 AC: 685 AN: 3250 Hom.: 85 Cov.: 0 AF XY: 0.189 AC XY: 331 AN XY: 1750

African (AFR) AF: 0.0536 AC: 3 AN: 56

American (AMR) AF: 0.234 AC: 15 AN: 64

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 21 AN: 86

East Asian (EAS) AF: 0.494 AC: 166 AN: 336

South Asian (SAS) AF: 0.143 AC: 8 AN: 56

European-Finnish (FIN) AF: 0.180 AC: 57 AN: 316

Middle Eastern (MID) AF: 0.143 AC: 2 AN: 14

European-Non Finnish (NFE) AF: 0.173 AC: 375 AN: 2166

Other (OTH) AF: 0.244 AC: 38 AN: 156

GnomAD4 genome AF: 0.168 AC: 25496 AN: 152182 Hom.: 2845 Cov.: 32 AF XY: 0.175 AC XY: 13044 AN XY: 74406

African (AFR) AF: 0.0413 AC: 1714 AN: 41538

American (AMR) AF: 0.296 AC: 4516 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 772 AN: 3470

East Asian (EAS) AF: 0.425 AC: 2192 AN: 5154

South Asian (SAS) AF: 0.206 AC: 991 AN: 4818

European-Finnish (FIN) AF: 0.220 AC: 2336 AN: 10606

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12326 AN: 68008

Other (OTH) AF: 0.192 AC: 406 AN: 2110

Alfa AF: 0.0892 Hom.: 145

Bravo AF: 0.169

Asia WGS AF: 0.255 AC: 885 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.2
DANN	Benign	0.64
PhyloP100		-0.48
PromoterAI		-0.090	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1800844; hg19: chr14-73603700;