rs362356

Variant names:

• chr14-73171921-G-C
• rs362356
• NM_000021.4:c.338+874G>C

Variant summary

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

The NM_000021.4(PSEN1):​c.338+874G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.056 in 152,164 control chromosomes in the GnomAD database, including 326 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 0.056 (326 hom., cov: 32)
• Consequence: PSEN1 NM_000021.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.147
• Publications: 6 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000021.4. 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.338+874G>C		intron	N/A	NP_000012.1	A0A024R6A3
	PSEN1	NM_007318.3		c.326+874G>C		intron	N/A	NP_015557.2	A0A0S2Z4D2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN1	ENST00000324501.10	TSL:1 MANE Select	c.338+874G>C		intron	N/A	ENSP00000326366.5	P49768-1
	PSEN1	ENST00000357710.8	TSL:1	c.326+874G>C		intron	N/A	ENSP00000350342.4	P49768-2
	PSEN1	ENST00000394164.5	TSL:1	c.326+874G>C		intron	N/A	ENSP00000377719.1	P49768-2

Frequencies

GnomAD3 genomes AF: 0.0561 AC: 8529 AN: 152046 Hom.: 326 Cov.: 32

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0417

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.00866

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.0687

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0886

Gnomad OTH AF: 0.0521

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

GnomAD4 genome AF: 0.0560 AC: 8528 AN: 152164 Hom.: 326 Cov.: 32 AF XY: 0.0533 AC XY: 3965 AN XY: 74392

African (AFR) AF: 0.0161 AC: 670 AN: 41518

American (AMR) AF: 0.0416 AC: 635 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 214 AN: 3468

East Asian (EAS) AF: 0.00868 AC: 45 AN: 5182

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4824

European-Finnish (FIN) AF: 0.0687 AC: 726 AN: 10572

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

European-Non Finnish (NFE) AF: 0.0886 AC: 6027 AN: 68002

Other (OTH) AF: 0.0516 AC: 109 AN: 2114

Alfa AF: 0.0713 Hom.: 41

Bravo AF: 0.0533

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.47
DANN	Benign	0.37
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs362356; hg19: chr14-73638629;