rs2068143

Positions:

• chr15-63296463-G-A

Variant summary

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

The NM_031301.4(APH1B):​c.479-5882G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 152,000 control chromosomes in the GnomAD database, including 12,448 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 0.37 (12448 hom., cov: 32)
• Consequence: APH1B NM_031301.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.28

Genes affected

APH1B (HGNC:24080): (aph-1 homolog B, gamma-secretase subunit) This gene encodes a multi-pass transmembrane protein that is a functional component of the gamma-secretase complex, which also contains presenilin and nicastrin. This protein represents a stabilizing cofactor for the presenilin holoprotein in the complex. The gamma-secretase complex catalyzes the cleavage of integral proteins such as notch receptors and beta-amyloid precursor protein. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APH1B	NM_031301.4	c.479-5882G>A		intron_variant		ENST00000261879.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APH1B	ENST00000261879.10	c.479-5882G>A		intron_variant		1	NM_031301.4	P1

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56356 AN: 151882 Hom.: 12419 Cov.: 32

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.341

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

GnomAD4 genome AF: 0.371 AC: 56430 AN: 152000 Hom.: 12448 Cov.: 32 AF XY: 0.372 AC XY: 27617 AN XY: 74312

Gnomad4 AFR AF: 0.618

Gnomad4 AMR AF: 0.378

Gnomad4 ASJ AF: 0.288

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.291

Gnomad4 NFE AF: 0.261

Gnomad4 OTH AF: 0.336

Alfa AF: 0.277 Hom.: 6948

Bravo AF: 0.385

Asia WGS AF: 0.241 AC: 840 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0040
DANN	Benign	0.64

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: rs2068143; hg19: chr15-63588662;