Variant 15-63305658-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_031301.4(APH1B):c.651T>G(p.Phe217Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0412 in 1,614,156 control chromosomes in the GnomAD database, including 2,441 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.049 ( 272 hom., cov: 33)

Exomes 𝑓: 0.040 ( 2169 hom. )

Consequence

APH1B
NM_031301.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0410

Variant links:

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]

APH1B links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024763942).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
APH1B	NM_031301.4 linkuse as main transcript	c.651T>G	p.Phe217Leu	missense_variant	6/6	ENST00000261879.10
APH1B	NM_001145646.2 linkuse as main transcript	c.528T>G	p.Phe176Leu	missense_variant	5/5
APH1B	XM_024450085.2 linkuse as main transcript	c.489T>G	p.Phe163Leu	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APH1B	ENST00000261879.10 linkuse as main transcript	c.651T>G	p.Phe217Leu	missense_variant	6/6	1	NM_031301.4	P1	Q8WW43-1

Frequencies

GnomAD3 genomes

AF:

0.0489

AC:

7441

AN:

152202

Hom.:

274

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0570

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0891

Gnomad ASJ

AF:

0.0409

Gnomad EAS

AF:

0.175

Gnomad SAS

AF:

0.0490

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0298

Gnomad OTH

AF:

0.0559

GnomAD3 exomes

AF:

0.0605

AC:

15196

AN:

251078

Hom.:

799

AF XY:

0.0572

AC XY:

7763

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.0622

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.0439

Gnomad EAS exome

AF:

0.163

Gnomad SAS exome

AF:

0.0452

Gnomad FIN exome

AF:

0.0300

Gnomad NFE exome

AF:

0.0297

Gnomad OTH exome

AF:

0.0522

GnomAD4 exome

AF:

0.0404

AC:

59015

AN:

1461836

Hom.:

2169

Cov.:

AF XY:

0.0404

AC XY:

29346

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0584

Gnomad4 AMR exome

AF:

0.139

Gnomad4 ASJ exome

AF:

0.0477

Gnomad4 EAS exome

AF:

0.197

Gnomad4 SAS exome

AF:

0.0481

Gnomad4 FIN exome

AF:

0.0303

Gnomad4 NFE exome

AF:

0.0294

Gnomad4 OTH exome

AF:

0.0482

GnomAD4 genome

AF:

0.0489

AC:

7450

AN:

152320

Hom.:

272

Cov.:

AF XY:

0.0496

AC XY:

3692

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0571

Gnomad4 AMR

AF:

0.0891

Gnomad4 ASJ

AF:

0.0409

Gnomad4 EAS

AF:

0.174

Gnomad4 SAS

AF:

0.0495

Gnomad4 FIN

AF:

0.0261

Gnomad4 NFE

AF:

0.0298

Gnomad4 OTH

AF:

0.0553

Alfa

AF:

0.0349

Hom.:

160

Bravo

AF:

0.0568

TwinsUK

AF:

0.0275

AC:

102

ALSPAC

AF:

0.0254

AC:

ESP6500AA

AF:

0.0554

AC:

244

ESP6500EA

AF:

0.0301

AC:

259

ExAC

AF:

0.0576

AC:

6993

Asia WGS

AF:

0.0950

AC:

329

AN:

3478

EpiCase

AF:

0.0304

EpiControl

AF:

0.0327

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.31

T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.73

T;T;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Benign

0.068

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.047

.;B;.

Vest4

0.072, 0.26

MutPred

0.50

.;Loss of glycosylation at S215 (P = 0.2232);.;

MPC

0.072

ClinPred

0.042

GERP RS

0.014

Varity_R

0.23

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over