rs35408871

Variant names:

• chr15-63290586-G-A
• rs35408871
• NM_031301.4:c.478+3040G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031301.4(APH1B):​c.478+3040G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,274 control chromosomes in the GnomAD database, including 2,044 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 0.15 (2044 hom., cov: 32)
• Consequence: APH1B NM_031301.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0610
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031301.4. 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
	APH1B	NM_031301.4	MANE Select	c.478+3040G>A		intron	N/A	NP_112591.2	Q8WW43-1
	APH1B	NM_001145646.2		c.355+3958G>A		intron	N/A	NP_001139118.1	Q8WW43-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APH1B	ENST00000261879.10	TSL:1 MANE Select	c.478+3040G>A		intron	N/A	ENSP00000261879.5	Q8WW43-1
	APH1B	ENST00000380343.8	TSL:1	c.355+3958G>A		intron	N/A	ENSP00000369700.4	Q8WW43-2
	APH1B	ENST00000559971.5	TSL:1	n.*554+3040G>A		intron	N/A	ENSP00000453516.1	H0YM95

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22717 AN: 152156 Hom.: 2043 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.151

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

GnomAD4 genome AF: 0.149 AC: 22740 AN: 152274 Hom.: 2044 Cov.: 32 AF XY: 0.156 AC XY: 11607 AN XY: 74468

African (AFR) AF: 0.143 AC: 5942 AN: 41558

American (AMR) AF: 0.144 AC: 2208 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 550 AN: 3472

East Asian (EAS) AF: 0.455 AC: 2352 AN: 5172

South Asian (SAS) AF: 0.289 AC: 1395 AN: 4832

European-Finnish (FIN) AF: 0.176 AC: 1861 AN: 10600

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7936 AN: 68018

Other (OTH) AF: 0.154 AC: 326 AN: 2114

Alfa AF: 0.145 Hom.: 744

Bravo AF: 0.147

Asia WGS AF: 0.376 AC: 1305 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.97
DANN	Benign	0.41
PhyloP100		-0.061
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35408871; hg19: chr15-63582785;