14-73219177-CA-TC

Variant names:

• chr14-73219177-CA-TC
• NM_000021.4:c.1292_1293delCAinsTC
• PSEN1 p.Ala431Val

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACMG Germline Pathogenicity v2019). PS1_ModeratePM1PM2PM5PP2

The NM_000021.4(PSEN1):c.1292_1293delCAinsTC (p.Ala431Val) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.83). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: Not reported in ClinVar
• Conservation: PhyloP100: 7.83
• Publications: 0 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: Likely_pathogenic. The variant received 9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, 0-star ClinVar pathogenic — moderate (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 0 stars).
	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×).

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.1292_1293delCAinsTC p.Ala431Val	missense	N/A	Prot: NP_000012.1 UniProt:
	PSEN1 NM_007318.3		c.1280_1281delCAinsTC p.Ala427Val	missense	N/A	Prot: NP_015557.2 UniProt:

PSEN1 NM_000021.4

MANE Select

HGVSc / HGVSpc.1292_1293delCAinsTCp.Ala431Val

Exon rankN/A

missense

Prot: NP_000012.1UniProt: A0A024R6A3P49768-1

PSEN1 NM_007318.3

HGVSc / HGVSpc.1280_1281delCAinsTCp.Ala427Val

Exon rankN/A

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.1292_1293delCAinsTC p.Ala431Val	missense	N/A	Prot: ENSP00000326366.5 UniProt:
	PSEN1 ENST00000357710.8	TSL:1	c.1280_1281delCAinsTC p.Ala427Val	missense	N/A	Prot: ENSP00000350342.4 UniProt:
	PSEN1 ENST00000394164.5	TSL:1	c.1280_1281delCAinsTC p.Ala427Val	missense	N/A	Prot: ENSP00000377719.1 UniProt:

PSEN1 ENST00000324501.10

TSL:1MANE Select

HGVSc / HGVSpc.1292_1293delCAinsTCp.Ala431Val

Exon rankN/A

missense

Prot: ENSP00000326366.5UniProt: P49768-1

PSEN1 ENST00000357710.8

TSL:1

HGVSc / HGVSpc.1280_1281delCAinsTCp.Ala427Val

Exon rankN/A

missense

Prot: ENSP00000350342.4UniProt: P49768-2

PSEN1 ENST00000394164.5

TSL:1

HGVSc / HGVSpc.1280_1281delCAinsTCp.Ala427Val

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	7.8

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr14-73685885;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar