chr14-73136423-C-T

Variant names:

• chr14-73136423-C-T
• rs1800839
• ENST00000557356.5:c.-161C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000557356.5(PSEN1):​c.-161C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.056 in 152,976 control chromosomes in the GnomAD database, including 324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (324 hom., cov: 33)
  • Exomes 𝑓: 0.054 (0 hom.)
• Consequence: PSEN1 ENST00000557356.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.71
• Publications: 9 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 14-73136423-C-T is Benign according to our data. Variant chr14-73136423-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0867 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000557356.5. 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
	PSEN1	NM_000021.4	MANE Select	c.-296C>T		upstream_gene	N/A	NP_000012.1	A0A024R6A3
	PSEN1	NM_007318.3		c.-296C>T		upstream_gene	N/A	NP_015557.2	A0A0S2Z4D2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN1	ENST00000557356.5	TSL:4	c.-161C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000451498.1	G3V3Z0
	PSEN1	ENST00000557356.5	TSL:4	c.-161C>T		5_prime_UTR	Exon 1 of 5	ENSP00000451498.1	G3V3Z0
	PSEN1	ENST00000324501.10	TSL:1 MANE Select	c.-296C>T		upstream_gene	N/A	ENSP00000326366.5	P49768-1

Frequencies

GnomAD3 genomes AF: 0.0561 AC: 8534 AN: 152196 Hom.: 324 Cov.: 33

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.0688

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0886

Gnomad OTH AF: 0.0522

GnomAD4 exome AF: 0.0544 AC: 36 AN: 662 Hom.: 0 Cov.: 0 AF XY: 0.0482 AC XY: 21 AN XY: 436

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 1 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 8

European-Finnish (FIN) AF: 0.0461 AC: 20 AN: 434

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0722 AC: 14 AN: 194

Other (OTH) AF: 0.125 AC: 1 AN: 8

GnomAD4 genome AF: 0.0560 AC: 8533 AN: 152314 Hom.: 324 Cov.: 33 AF XY: 0.0533 AC XY: 3968 AN XY: 74478

African (AFR) AF: 0.0162 AC: 672 AN: 41586

American (AMR) AF: 0.0415 AC: 635 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 215 AN: 3468

East Asian (EAS) AF: 0.00869 AC: 45 AN: 5180

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4830

European-Finnish (FIN) AF: 0.0688 AC: 730 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0886 AC: 6025 AN: 68022

Other (OTH) AF: 0.0517 AC: 109 AN: 2110

Alfa AF: 0.0627 Hom.: 177

Bravo AF: 0.0532

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Early-onset autosomal dominant Alzheimer disease (1)
-	-	1	not provided (1)
-	-	1	Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.81
PhyloP100		1.7
PromoterAI		-0.27	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1800839; hg19: chr14-73603131;