1-150269789-G-C

Variant names:

• chr1-150269789-G-C
• rs3754048
• ENST00000369102.5:c.-150+969G>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000369102.5(C1orf54):​c.-150+969G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 152,038 control chromosomes in the GnomAD database, including 9,847 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 0.35 (9847 hom., cov: 32)
• Consequence: C1orf54 ENST00000369102.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65

Genes affected

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:):

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124904414	XM_047438213.1	c.357-460C>G		intron_variant	Intron 1 of 1		XP_047294169.1
C1orf54	XM_047430446.1	c.-150+969G>C		intron_variant	Intron 1 of 7		XP_047286402.1
C1orf54	XM_047430455.1	c.-150+969G>C		intron_variant	Intron 1 of 7		XP_047286411.1
C1orf54	XM_047430461.1	c.-150+969G>C		intron_variant	Intron 1 of 6		XP_047286417.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1orf54	ENST00000369102.5	c.-150+969G>C		intron_variant	Intron 1 of 7	5		ENSP00000358098.1
APH1A	ENST00000493092.1	n.-209C>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52924 AN: 151920 Hom.: 9833 Cov.: 32

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.359

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.348 AC: 52973 AN: 152038 Hom.: 9847 Cov.: 32 AF XY: 0.354 AC XY: 26285 AN XY: 74340

Gnomad4 AFR AF: 0.410

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.598

Gnomad4 SAS AF: 0.468

Gnomad4 FIN AF: 0.282

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.361

Alfa AF: 0.159 Hom.: 284

Bravo AF: 0.359

Asia WGS AF: 0.496 AC: 1724 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.82
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs3754048; hg19: chr1-150242189;