NM_001077628.3:c.-20C>A

Variant names:

• chr1-150268830-G-T
• rs2275780
• NM_001077628.3:c.-20C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_Moderate BA1

The NM_001077628.3(APH1A):​c.-20C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,602,014 control chromosomes in the GnomAD database, including 13,362 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (1093 hom., cov: 31)
  • Exomes 𝑓: 0.12 (12269 hom.)
• Consequence: APH1A NM_001077628.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.08
• Publications: 14 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]

LOC124904414 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APH1A	NM_001077628.3	c.-20C>A		5_prime_UTR_variant	Exon 1 of 7	ENST00000369109.8	NP_001071096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APH1A	ENST00000369109.8	c.-20C>A		5_prime_UTR_variant	Exon 1 of 7	1	NM_001077628.3	ENSP00000358105.3

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15338 AN: 152056 Hom.: 1094 Cov.: 31

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.136 AC: 30476 AN: 223536 AF XY: 0.137

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.360

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.123 AC: 179019 AN: 1449840 Hom.: 12269 Cov.: 30 AF XY: 0.124 AC XY: 89160 AN XY: 720306

African (AFR) AF: 0.0209 AC: 695 AN: 33322

American (AMR) AF: 0.128 AC: 5457 AN: 42714

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3257 AN: 25902

East Asian (EAS) AF: 0.334 AC: 13138 AN: 39296

South Asian (SAS) AF: 0.139 AC: 11825 AN: 84932

European-Finnish (FIN) AF: 0.119 AC: 6181 AN: 51988

Middle Eastern (MID) AF: 0.143 AC: 819 AN: 5746

European-Non Finnish (NFE) AF: 0.117 AC: 129633 AN: 1105998

Other (OTH) AF: 0.134 AC: 8014 AN: 59942

GnomAD4 genome AF: 0.101 AC: 15325 AN: 152174 Hom.: 1093 Cov.: 31 AF XY: 0.104 AC XY: 7716 AN XY: 74394

African (AFR) AF: 0.0271 AC: 1125 AN: 41546

American (AMR) AF: 0.114 AC: 1751 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 389 AN: 3472

East Asian (EAS) AF: 0.351 AC: 1797 AN: 5126

South Asian (SAS) AF: 0.146 AC: 706 AN: 4830

European-Finnish (FIN) AF: 0.121 AC: 1278 AN: 10602

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.115 AC: 7834 AN: 67986

Other (OTH) AF: 0.136 AC: 287 AN: 2110

Alfa AF: 0.0928 Hom.: 723

Bravo AF: 0.0993

Asia WGS AF: 0.234 AC: 809 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		2.1
PromoterAI		-0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.82		Position offset: -2

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

Other links and lift over

dbSNP: rs2275780; hg19: chr1-150241230; COSMIC: COSV52530368; COSMIC: COSV52530368;