rs362355

chr14-73171253-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000021.4(PSEN1):c.338+206T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0829 in 152,192 control chromosomes in the GnomAD database, including 1,158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.083 (1158 hom., cov: 32)
• Consequence: PSEN1 NM_000021.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.639

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-73171253-T-C is Benign according to our data. Variant chr14-73171253-T-C is described in ClinVar as [Benign]. Clinvar id is 1295802.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	NM_000021.4	c.338+206T>C		intron_variant		ENST00000324501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000324501.10	c.338+206T>C		intron_variant		1	NM_000021.4	P4

Frequencies

GnomAD3 genomes AF: 0.0827 AC: 12583 AN: 152074 Hom.: 1151 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.0493

Gnomad SAS AF: 0.0742

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0597

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0829 AC: 12616 AN: 152192 Hom.: 1158 Cov.: 32 AF XY: 0.0823 AC XY: 6122 AN XY: 74418

Gnomad4 AFR AF: 0.233

Gnomad4 AMR AF: 0.0454

Gnomad4 ASJ AF: 0.0429

Gnomad4 EAS AF: 0.0496

Gnomad4 SAS AF: 0.0747

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0586

Alfa AF: 0.0576 Hom.: 98

Bravo AF: 0.0894

Asia WGS AF: 0.0590 AC: 207 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	9.9
Dann	Benign	0.72

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: rs362355; hg19: chr14-73637961;