Variant 1-150267790-C-CTGGGG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PVS1_ModeratePP3BP6_Moderate

The NM_001077628.3(APH1A):c.285-2_285-1insCCCCA variant causes a splice acceptor change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.014 ( 61 hom., cov: 31)

Exomes 𝑓: 0.0015 ( 40 hom. )

Failed GnomAD Quality Control

Consequence

APH1A
NM_001077628.3 splice_acceptor

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.80

Variant links:

Genes affected

APH1A (HGNC:29509): (aph-1 homolog A, gamma-secretase subunit) This gene encodes a component of the gamma secretase complex that cleaves integral membrane proteins such as Notch receptors and beta-amyloid precursor protein. The gamma secretase complex contains this gene product, or the paralogous anterior pharynx defective 1 homolog B (APH1B), along with the presenilin, nicastrin, and presenilin enhancer-2 proteins. The precise function of this seven-transmembrane-domain protein is unknown though it is suspected of facilitating the association of nicastrin and presenilin in the gamma secretase complex as well as interacting with substrates of the gamma secretase complex prior to their proteolytic processing. Polymorphisms in a promoter region of this gene have been associated with an increased risk for developing sporadic Alzheimer's disease. Alternative splicing results in multiple protein-coding and non-protein-coding transcript variants. [provided by RefSeq, Aug 2011]

APH1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0914787 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.7, offset of 0 (no position change), new splice context is: cccaccccaccccaccccAGgaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP6

Variant 1-150267790-C-CTGGGG is Benign according to our data. Variant chr1-150267790-C-CTGGGG is described in ClinVar as [Likely_benign]. Clinvar id is 3042111.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APH1A	NM_001077628.3 linkuse as main transcript	c.285-2_285-1insCCCCA		splice_acceptor_variant		ENST00000369109.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APH1A	ENST00000369109.8 linkuse as main transcript	c.285-2_285-1insCCCCA		splice_acceptor_variant		1	NM_001077628.3	P1	Q96BI3-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

2107

AN:

148884

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0496

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

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:

0.0000594

Gnomad OTH

AF:

0.0111

GnomAD3 exomes

AF:

0.00342

AC:

848

AN:

248282

Hom.:

AF XY:

0.00255

AC XY:

344

AN XY:

134792

show subpopulations

Gnomad AFR exome

AF:

0.0510

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000295

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000621

Gnomad OTH exome

AF:

0.000827

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00147

AC:

1952

AN:

1326364

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

826

AN XY:

662352

show subpopulations

Gnomad4 AFR exome

AF:

0.0530

Gnomad4 AMR exome

AF:

0.00242

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000310

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000327

Gnomad4 OTH exome

AF:

0.00340

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0142

AC:

2115

AN:

149026

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

950

AN XY:

72850

show subpopulations

Gnomad4 AFR

AF:

0.0496

Gnomad4 AMR

AF:

0.00490

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000594

Gnomad4 OTH

AF:

0.0110

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

APH1A-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over