chr1-150267790-C-CTGGGG

Position:

• chr1-150267790-C-CTGGGG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PVS1_Moderate BP6

The NM_001077628.3(APH1A):​c.285-6_285-2dupCCCCA variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely benign (no stars).

• 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, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.80

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 (HGNC:):

ACMG classification

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.
• 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 no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APH1A	NM_001077628.3	c.285-6_285-2dupCCCCA		splice_acceptor_variant, intron_variant		ENST00000369109.8	NP_001071096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APH1A	ENST00000369109.8	c.285-6_285-2dupCCCCA		splice_acceptor_variant, intron_variant		1	NM_001077628.3	ENSP00000358105.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2107 AN: 148884 Hom.: 61 Cov.: 31 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.: 15 AF XY: 0.00255 AC XY: 344 AN XY: 134792

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.: 40 Cov.: 35 AF XY: 0.00125 AC XY: 826 AN XY: 662352

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.: 61 Cov.: 31 AF XY: 0.0130 AC XY: 950 AN XY: 72850

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: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

APH1A-related disorder Benign:1

Likely benign, no assertion criteria provided

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199564486; hg19: chr1-150240190;