Genetic Variant APH1B:p.Pro29Gln (chr15-63277709-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_031301.4(APH1B):c.86C>A(p.Pro29Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000754 in 1,459,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

APH1B
NM_031301.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.66

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 Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APH1B	NM_031301.4 link	c.86C>A	p.Pro29Gln	missense_variant	Exon 1 of 6	ENST00000261879.10	NP_112591.2	Q8WW43-1
APH1B	NM_001145646.2 link	c.86C>A	p.Pro29Gln	missense_variant	Exon 1 of 5		NP_001139118.1	Q8WW43-2
APH1B	XM_011522105.4 link	c.86C>A	p.Pro29Gln	missense_variant	Exon 1 of 6		XP_011520407.1
APH1B	XR_007064490.1 link	n.105C>A		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APH1B	ENST00000261879.10 link	c.86C>A	p.Pro29Gln	missense_variant	Exon 1 of 6	1	NM_031301.4	ENSP00000261879.5		Q8WW43-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247494

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1459342

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726122

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.86C>A (p.P29Q) alteration is located in exon 1 (coding exon 1) of the APH1B gene. This alteration results from a C to A substitution at nucleotide position 86, causing the proline (P) at amino acid position 29 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Benign

0.92

DEOGEN2

Uncertain

0.73

D;.;D

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

-0.013

MutationAssessor

Uncertain

2.8

M;M;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.7

D;D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.71

MutPred

0.72

Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);

MVP

0.87

MPC

0.32

ClinPred

1.0

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.73

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: 0

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over