14-73170824-AACG-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PM4_Supporting BS2

The NM_000021.4(PSEN1):c.118_120del(p.Asp40del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000236 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: PSEN1 NM_000021.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.68

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a chain Presenilin-1 NTF subunit (size 297) in uniprot entity PSN1_HUMAN there are 288 pathogenic changes around while only 8 benign (97%) in NM_000021.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000021.4. Strenght limited to Supporting due to length of the change: 1aa.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	NM_000021.4	c.118_120del	p.Asp40del	inframe_deletion	4/12	ENST00000324501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000324501.10	c.118_120del	p.Asp40del	inframe_deletion	4/12	1	NM_000021.4	P4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251344 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135878

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: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000248 AC: 363 AN: 1461768 Hom.: 0 AF XY: 0.000270 AC XY: 196 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000302

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74500

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000106

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2023

Experimental studies have shown that this variant affects PSEN1 function (PMID: 27930341, 32087291). This variant, c.118_120del, results in the deletion of 1 amino acid(s) of the PSEN1 protein (p.Asp40del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs759538127, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of Alzheimer disease (PMID: 24463146, 32917274, 35949106). ClinVar contains an entry for this variant (Variation ID: 1505666). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

PSEN1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2023

The PSEN1 c.118_120delGAC variant is predicted to result in an in-frame deletion (p.Asp40del). This variant has been found in a patient with early onset Alzheimer disease, but no further segregation study was performed (Nygaard et al. 2014. PubMed ID: 24463146). This variant may affect the protein function, but the pathogenicity of the variant has not been elucidated (Sun et al. 2017. PubMed ID: 27930341). This variant is reported in 0.033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-73637532-AACG-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs759538127; hg19: chr14-73637532;