14-73148066-T-A

Variant names:

• chr14-73148066-T-A
• NM_000021.4:c.47T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000021.4(PSEN1):​c.47T>A​(p.Met16Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSEN1 NM_000021.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Presenilin-1 NTF subunit (size 297) in uniprot entity PSN1_HUMAN there are 186 pathogenic changes around while only 3 benign (98%) in NM_000021.4
• 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 acne inversa, familial, 3, dilated cardiomyopathy, Alzheimer disease 3, early-onset autosomal dominant Alzheimer disease, semantic dementia, Pick disease, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1U, behavioral variant of frontotemporal dementia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41198707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN1	NM_000021.4	c.47T>A	p.Met16Lys	missense_variant	Exon 3 of 12	ENST00000324501.10	NP_000012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10	c.47T>A	p.Met16Lys	missense_variant	Exon 3 of 12	1	NM_000021.4	ENSP00000326366.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461784 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	22
DANN	Benign	0.71
DEOGEN2	Benign	0.016	T;T;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D;D;D;.;D;D;D;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.8	.;.;.;.;.;.;.;.;L;L;L;.;.;.;.;L;.;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.4	N;D;N;N;N;N;N;D;N;N;N;N;N;N;D;N;D;N
REVEL	Uncertain	0.58
Sift	Benign	0.092	T;D;T;T;T;T;T;D;T;T;T;T;D;T;D;T;D;T
Sift4G	Benign	0.68	T;D;T;T;T;T;T;D;T;T;T;T;T;T;D;T;D;T
Polyphen		0.15, 0.0030, 0.0010	.;.;.;.;.;.;.;.;B;B;B;.;.;.;.;B;.;.
Vest4		0.67, 0.64, 0.61, 0.60
MutPred		0.34		Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);Gain of ubiquitination at M16 (P = 7e-04);
MVP		0.99
MPC		0.82
ClinPred		0.77	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.43

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-73614774;