rs199564486

Variant names:

• chr1-150267790-CTGGGG-C
• rs199564486
• NM_001077628.3:c.285-6_285-2delCCCCA

Your query was ambiguous. Multiple possible variants found:

• chr1-150267790-CTGGGG-C
• chr1-150267790-CTGGGG-CTGGGGTGGGG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001077628.3(APH1A):​c.285-6_285-2delCCCCA variant causes a splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000271 in 1,475,016 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: APH1A NM_001077628.3 splice_acceptor, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80
• Publications: 2 publications found

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]

C1orf54 (HGNC:26258): (chromosome 1 open reading frame 54) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.092731826 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.3, offset of 0 (no position change), new splice context is: tttcccctaccccaccccAGgaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077628.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APH1A	NM_001077628.3	MANE Select	c.285-6_285-2delCCCCA		splice_acceptor splice_region intron	N/A	NP_001071096.1	Q96BI3-1
	APH1A	NM_016022.4		c.285-6_285-2delCCCCA		splice_acceptor splice_region intron	N/A	NP_057106.2	Q96BI3-2
	APH1A	NM_001243772.2		c.148+162_148+166delCCCCA		intron	N/A	NP_001230701.1	Q96BI3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APH1A	ENST00000369109.8	TSL:1 MANE Select	c.285-6_285-2delCCCCA		splice_acceptor splice_region intron	N/A	ENSP00000358105.3	Q96BI3-1
	APH1A	ENST00000360244.8	TSL:1	c.285-6_285-2delCCCCA		splice_acceptor splice_region intron	N/A	ENSP00000353380.4	Q96BI3-2
	APH1A	ENST00000877470.1		c.285-6_285-2delCCCCA		splice_acceptor splice_region intron	N/A	ENSP00000547529.1

Frequencies

GnomAD3 genomes AF: 0.00000671 AC: 1 AN: 149014 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000226 AC: 3 AN: 1326002 Hom.: 0 AF XY: 0.00000453 AC XY: 3 AN XY: 662176

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30242

American (AMR) AF: 0.00 AC: 0 AN: 42566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23530

East Asian (EAS) AF: 0.00 AC: 0 AN: 34818

South Asian (SAS) AF: 0.00 AC: 0 AN: 83964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5316

European-Non Finnish (NFE) AF: 0.00000297 AC: 3 AN: 1008576

Other (OTH) AF: 0.00 AC: 0 AN: 53836

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000671 AC: 1 AN: 149014 Hom.: 0 Cov.: 31 AF XY: 0.0000137 AC XY: 1 AN XY: 72794

African (AFR) AF: 0.00 AC: 0 AN: 40562

American (AMR) AF: 0.00 AC: 0 AN: 15084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 4884

South Asian (SAS) AF: 0.00 AC: 0 AN: 4534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67350

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8

Splicing

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

Other links and lift over

dbSNP: rs199564486; hg19: chr1-150240190;