NM_001077628.3:c.285-6_285-2dupCCCCA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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 1 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 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 VariationId is 3042111.Status of the report is no_assertion_criteria_provided, 0 stars.

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_285-2dupCCCCA		splice_acceptor intron	N/A	NP_001071096.1	Q96BI3-1
	APH1A	NM_016022.4		c.285-6_285-2dupCCCCA		splice_acceptor intron	N/A	NP_057106.2	Q96BI3-2
	APH1A	NM_001243772.2		c.148+162_148+166dupCCCCA		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.285-2_285-1insCCCCA		splice_acceptor intron	N/A	ENSP00000358105.3	Q96BI3-1
	APH1A	ENST00000360244.8	TSL:1	c.285-2_285-1insCCCCA		splice_acceptor intron	N/A	ENSP00000353380.4	Q96BI3-2
	APH1A	ENST00000877470.1		c.285-2_285-1insCCCCA		splice_acceptor intron	N/A	ENSP00000547529.1

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2107 AN: 148884 Hom.: 61 Cov.: 31

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

GnomAD2 exomes AF: 0.00342 AC: 848 AN: 248282 AF XY: 0.00255

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 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

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

African (AFR) AF: 0.0530 AC: 1598 AN: 30134

American (AMR) AF: 0.00242 AC: 103 AN: 42566

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 34820

South Asian (SAS) AF: 0.000310 AC: 26 AN: 83972

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

Middle Eastern (MID) AF: 0.00169 AC: 9 AN: 5316

European-Non Finnish (NFE) AF: 0.0000327 AC: 33 AN: 1009030

Other (OTH) AF: 0.00340 AC: 183 AN: 53842

⚠️ 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 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

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

African (AFR) AF: 0.0496 AC: 2014 AN: 40574

American (AMR) AF: 0.00490 AC: 74 AN: 15096

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4874

South Asian (SAS) AF: 0.00 AC: 0 AN: 4536

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000594 AC: 4 AN: 67346

Other (OTH) AF: 0.0110 AC: 23 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000923 Hom.: 0

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	APH1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=84/16	polymorphism

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;