rs165932

Variant names:

• chr14-73198145-G-T
• rs165932
• NM_000021.4:c.868+16G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-73198145-G-T
• chr14-73198145-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000021.4(PSEN1):​c.868+16G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,444,742 control chromosomes in the GnomAD database, including 246,941 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29718 hom., cov: 32)
  • Exomes 𝑓: 0.58 (217223 hom.)
• Consequence: PSEN1 NM_000021.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.906
• Publications: 41 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 14-73198145-G-T is Benign according to our data. Variant chr14-73198145-G-T is described in ClinVar as Benign. ClinVar VariationId is 254714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.733 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.868+16G>T		intron	N/A	NP_000012.1	A0A024R6A3
	PSEN1	NM_007318.3		c.856+16G>T		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.868+16G>T		intron	N/A	ENSP00000326366.5	P49768-1
	PSEN1	ENST00000357710.8	TSL:1	c.856+16G>T		intron	N/A	ENSP00000350342.4	P49768-2
	PSEN1	ENST00000394164.5	TSL:1	c.856+16G>T		intron	N/A	ENSP00000377719.1	P49768-2

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93871 AN: 151934 Hom.: 29659 Cov.: 32

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.639

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.609

GnomAD2 exomes AF: 0.609 AC: 145384 AN: 238688 AF XY: 0.609

Gnomad AFR exome AF: 0.747

Gnomad AMR exome AF: 0.692

Gnomad ASJ exome AF: 0.586

Gnomad EAS exome AF: 0.643

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.552

Gnomad OTH exome AF: 0.595

GnomAD4 exome AF: 0.576 AC: 745102 AN: 1292690 Hom.: 217223 Cov.: 19 AF XY: 0.580 AC XY: 377723 AN XY: 650824

African (AFR) AF: 0.742 AC: 22507 AN: 30340

American (AMR) AF: 0.687 AC: 30088 AN: 43782

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 14586 AN: 24876

East Asian (EAS) AF: 0.642 AC: 24995 AN: 38912

South Asian (SAS) AF: 0.730 AC: 59832 AN: 81978

European-Finnish (FIN) AF: 0.483 AC: 25366 AN: 52554

Middle Eastern (MID) AF: 0.578 AC: 3114 AN: 5390

European-Non Finnish (NFE) AF: 0.555 AC: 532624 AN: 960166

Other (OTH) AF: 0.585 AC: 31990 AN: 54692

GnomAD4 genome AF: 0.618 AC: 93991 AN: 152052 Hom.: 29718 Cov.: 32 AF XY: 0.618 AC XY: 45934 AN XY: 74318

African (AFR) AF: 0.739 AC: 30660 AN: 41464

American (AMR) AF: 0.655 AC: 10011 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 2074 AN: 3468

East Asian (EAS) AF: 0.640 AC: 3308 AN: 5172

South Asian (SAS) AF: 0.728 AC: 3511 AN: 4820

European-Finnish (FIN) AF: 0.472 AC: 4984 AN: 10556

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37580 AN: 67976

Other (OTH) AF: 0.608 AC: 1284 AN: 2112

Alfa AF: 0.583 Hom.: 35636

Bravo AF: 0.634

Asia WGS AF: 0.645 AC: 2241 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Acne inversa, familial, 3 (1)
-	-	1	Alzheimer disease 3 (1)
-	-	1	Dilated cardiomyopathy 1U (1)
-	-	1	Frontotemporal dementia (1)
-	-	1	Pick disease (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	-0.70
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		-0.91
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: rs165932; hg19: chr14-73664853; COSMIC: COSV56194831;