14-73211811-A-T

Variant names:

• chr14-73211811-A-T
• rs121917809
• NM_000021.4:c.998A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000021.4(PSEN1):​c.998A>T​(p.Asp333Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D333G) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: PSEN1 NM_000021.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.52
• Publications: 24 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PSEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 2.1558 (below the threshold of 3.09). Trascript score misZ: 3.0986 (above the threshold of 3.09). GenCC associations: The gene is linked to early-onset autosomal dominant Alzheimer disease, Pick disease, semantic dementia, Alzheimer disease 3, familial isolated dilated cardiomyopathy, dilated cardiomyopathy, dilated cardiomyopathy 1U, acne inversa, familial, 3, behavioral variant of frontotemporal dementia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

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.998A>T	p.Asp333Val	missense	Exon 10 of 12	NP_000012.1	A0A024R6A3
	PSEN1	NM_007318.3		c.986A>T	p.Asp329Val	missense	Exon 10 of 12	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.998A>T	p.Asp333Val	missense	Exon 10 of 12	ENSP00000326366.5	P49768-1
	PSEN1	ENST00000357710.8	TSL:1	c.986A>T	p.Asp329Val	missense	Exon 10 of 12	ENSP00000350342.4	P49768-2
	PSEN1	ENST00000394164.5	TSL:1	c.986A>T	p.Asp329Val	missense	Exon 10 of 12	ENSP00000377719.1	P49768-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.015	D
Sift4G	Benign	0.12	T
Polyphen		0.11	B
Vest4		0.76
MutPred		0.49		Gain of catalytic residue at F336 (P = 0)
MVP		0.97
MPC		1.7
ClinPred		0.95	D
GERP RS		6.1
Varity_R		0.36
gMVP		0.73
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121917809; hg19: chr14-73678519;