1-150268096-C-A

Variant names:

• chr1-150268096-C-A
• rs1157822339
• NM_001077628.3:c.145G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001077628.3(APH1A):​c.145G>T​(p.Ala49Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APH1A NM_001077628.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.825
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12903592).

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.145G>T	p.Ala49Ser	missense	Exon 2 of 7	NP_001071096.1	Q96BI3-1
	APH1A	NM_016022.4		c.145G>T	p.Ala49Ser	missense	Exon 2 of 6	NP_057106.2	Q96BI3-2
	APH1A	NM_001243772.2		c.114-105G>T		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.145G>T	p.Ala49Ser	missense	Exon 2 of 7	ENSP00000358105.3	Q96BI3-1
	APH1A	ENST00000360244.8	TSL:1	c.145G>T	p.Ala49Ser	missense	Exon 2 of 6	ENSP00000353380.4	Q96BI3-2
	APH1A	ENST00000877470.1		c.145G>T	p.Ala49Ser	missense	Exon 2 of 7	ENSP00000547529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.82
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.060
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.021	B
Vest4		0.18
MutPred		0.66		Loss of stability (P = 0.1275)
MVP		0.45
MPC		0.79
ClinPred		0.43	T
GERP RS		5.0
PromoterAI		-0.059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.57
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1157822339; hg19: chr1-150240496;