rs165935

Variant names:

• chr14-73220436-C-T
• rs165935
• NM_000021.4:c.*1147C>T

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.*1147C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 152,500 control chromosomes in the GnomAD database, including 29,632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29577 hom., cov: 32)
  • Exomes 𝑓: 0.52 (55 hom.)
• Consequence: PSEN1 NM_000021.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.852
• Publications: 11 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=-0.83).
• BP6: Variant 14-73220436-C-T is Benign according to our data. Variant chr14-73220436-C-T is described in ClinVar as Benign. ClinVar VariationId is 313962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.723 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN1	NM_000021.4	MANE Select	c.*1147C>T		3_prime_UTR	Exon 12 of 12	NP_000012.1
	PSEN1	NM_007318.3		c.*1147C>T		3_prime_UTR	Exon 12 of 12	NP_015557.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN1	ENST00000324501.10	TSL:1 MANE Select	c.*1147C>T		3_prime_UTR	Exon 12 of 12	ENSP00000326366.5
	PSEN1	ENST00000554995.2	TSL:2	n.3301C>T		non_coding_transcript_exon	Exon 5 of 5
	PSEN1	ENST00000556066.2	TSL:3	n.2977C>T		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93741 AN: 151962 Hom.: 29521 Cov.: 32

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.607

GnomAD4 exome AF: 0.524 AC: 220 AN: 420 Hom.: 55 Cov.: 0 AF XY: 0.516 AC XY: 131 AN XY: 254

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.522 AC: 215 AN: 412

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.667 AC: 4 AN: 6

GnomAD4 genome AF: 0.617 AC: 93858 AN: 152080 Hom.: 29577 Cov.: 32 AF XY: 0.618 AC XY: 45913 AN XY: 74346

African (AFR) AF: 0.729 AC: 30253 AN: 41474

American (AMR) AF: 0.658 AC: 10062 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 2074 AN: 3472

East Asian (EAS) AF: 0.662 AC: 3427 AN: 5176

South Asian (SAS) AF: 0.727 AC: 3503 AN: 4816

European-Finnish (FIN) AF: 0.480 AC: 5065 AN: 10552

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37619 AN: 67982

Other (OTH) AF: 0.606 AC: 1279 AN: 2112

Alfa AF: 0.585 Hom.: 13476

Bravo AF: 0.631

Asia WGS AF: 0.650 AC: 2259 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Alzheimer disease 3 (1)
-	-	1	Dilated cardiomyopathy 1U (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.65
DANN	Benign	0.28
PhyloP100		-0.85
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: rs165935; hg19: chr14-73687144;