NM_000021.4:c.1292C>T

Variant names:

• chr14-73219177-C-T
• rs63750083
• NM_000021.4:c.1292C>T
• PSEN1 p.Ala431Val

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5PP2PP3_ModeratePP5

The NM_000021.4(PSEN1):c.1292C>T (p.Ala431Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.83). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.A431E: Pathogenic (ClinVar VariationId 18155, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSEN1 NM_000021.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 7.83
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Pick disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• semantic dementia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• familial dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: G2P

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 10 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 13 pathogenic, 1 benign (OR vs. background: 45.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.A431E: Pathogenic (ClinVar VariationId 18155, 2 stars)
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 3.106). ClinVar shows strong pathogenic missense enrichment: 151 P/LP and 12 B/LB missense entries (ratio 12.6×).
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000021.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PSEN1 NM_000021.4	MANE Select	c.1292C>T p.Ala431Val	missense	Exon 12 of 12	Prot: NP_000012.1 UniProt:
	PSEN1 NM_007318.3		c.1280C>T p.Ala427Val	missense	Exon 12 of 12	Prot: NP_015557.2 UniProt:

PSEN1 NM_000021.4

MANE Select

HGVSc / HGVSpc.1292C>Tp.Ala431Val

Exon rankExon 12 of 12

missense

Prot: NP_000012.1UniProt: A0A024R6A3P49768-1

PSEN1 NM_007318.3

HGVSc / HGVSpc.1280C>Tp.Ala427Val

Exon rankExon 12 of 12

missense

Prot: NP_015557.2UniProt: P49768-2A0A0S2Z4D2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PSEN1 ENST00000324501.10	TSL:1MANE Select	c.1292C>T p.Ala431Val	missense	Exon 12 of 12	Prot: ENSP00000326366.5 UniProt:
	PSEN1 ENST00000357710.8	TSL:1	c.1280C>T p.Ala427Val	missense	Exon 12 of 12	Prot: ENSP00000350342.4 UniProt:
	PSEN1 ENST00000394164.5	TSL:1	c.1280C>T p.Ala427Val	missense	Exon 12 of 12	Prot: ENSP00000377719.1 UniProt:

PSEN1 ENST00000324501.10

TSL:1MANE Select

HGVSc / HGVSpc.1292C>Tp.Ala431Val

Exon rankExon 12 of 12

missense

Prot: ENSP00000326366.5UniProt: P49768-1

PSEN1 ENST00000357710.8

TSL:1

HGVSc / HGVSpc.1280C>Tp.Ala427Val

Exon rankExon 12 of 12

missense

Prot: ENSP00000350342.4UniProt: P49768-2

PSEN1 ENST00000394164.5

TSL:1

HGVSc / HGVSpc.1280C>Tp.Ala427Val

Exon rankExon 12 of 12

missense

Prot: ENSP00000377719.1UniProt: P49768-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Frontotemporal dementia (1)
-	1	-	not provided (2)
1	-	-	Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-9.0
GPN-Star score	N/A	9.0
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.98	D
Mutation Taster	N/A	0/100	disease causing
MutationAssessor	Pathogenic	3.7	H
PhyloP100	Pathogenic	7.8
popEVE	Benign	-4.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Varity_R	N/A	0.79
VESM-3B	Benign	-9.9

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.040	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs63750083;

hg19: chr14-73685885;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar