chr14-73198010-T-C

Variant names:

• chr14-73198010-T-C
• rs3025786
• NM_000021.4:c.770-21T>C

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.770-21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0438 in 1,426,226 control chromosomes in the GnomAD database, including 1,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (138 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1517 hom.)
• Consequence: PSEN1 NM_000021.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.18
• Publications: 7 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=-0.81).
• BP6: Variant 14-73198010-T-C is Benign according to our data. Variant chr14-73198010-T-C is described in ClinVar as [Benign]. Clinvar id is 1280880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN1	NM_000021.4	c.770-21T>C		intron_variant	Intron 7 of 11	ENST00000324501.10	NP_000012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10	c.770-21T>C		intron_variant	Intron 7 of 11	1	NM_000021.4	ENSP00000326366.5

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5427 AN: 152198 Hom.: 140 Cov.: 32

Gnomad AFR AF: 0.00907

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0414

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0547

Gnomad OTH AF: 0.0512

GnomAD2 exomes AF: 0.0353 AC: 8593 AN: 243740 AF XY: 0.0360

Gnomad AFR exome AF: 0.00704

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0310

Gnomad EAS exome AF: 0.000386

Gnomad FIN exome AF: 0.0282

Gnomad NFE exome AF: 0.0552

Gnomad OTH exome AF: 0.0410

GnomAD4 exome AF: 0.0447 AC: 56986 AN: 1273910 Hom.: 1517 Cov.: 18 AF XY: 0.0443 AC XY: 28468 AN XY: 643116

African (AFR) AF: 0.00759 AC: 227 AN: 29914

American (AMR) AF: 0.0297 AC: 1314 AN: 44218

Ashkenazi Jewish (ASJ) AF: 0.0316 AC: 780 AN: 24696

East Asian (EAS) AF: 0.000180 AC: 7 AN: 38850

South Asian (SAS) AF: 0.0127 AC: 1042 AN: 81836

European-Finnish (FIN) AF: 0.0288 AC: 1502 AN: 52156

Middle Eastern (MID) AF: 0.0747 AC: 405 AN: 5424

European-Non Finnish (NFE) AF: 0.0524 AC: 49368 AN: 942772

Other (OTH) AF: 0.0433 AC: 2341 AN: 54044

GnomAD4 genome AF: 0.0356 AC: 5420 AN: 152316 Hom.: 138 Cov.: 32 AF XY: 0.0342 AC XY: 2544 AN XY: 74484

African (AFR) AF: 0.00904 AC: 376 AN: 41578

American (AMR) AF: 0.0413 AC: 632 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0354 AC: 123 AN: 3472

East Asian (EAS) AF: 0.000770 AC: 4 AN: 5192

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4828

European-Finnish (FIN) AF: 0.0266 AC: 283 AN: 10620

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0546 AC: 3716 AN: 68016

Other (OTH) AF: 0.0497 AC: 105 AN: 2112

Alfa AF: 0.0445 Hom.: 135

Bravo AF: 0.0367

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.4
DANN	Benign	0.60
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3025786; hg19: chr14-73664718;