Variant chr15-63277666-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_031301.4(APH1B):c.43G>C(p.Gly15Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,210 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: 28)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

APH1B
NM_031301.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.27

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:

APH1B (HGNC:):

APH1B links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APH1B	NM_031301.4 linkuse as main transcript	c.43G>C	p.Gly15Arg	missense_variant	1/6	ENST00000261879.10	NP_112591.2	Q8WW43-1
APH1B	NM_001145646.2 linkuse as main transcript	c.43G>C	p.Gly15Arg	missense_variant	1/5		NP_001139118.1	Q8WW43-2
APH1B	XM_011522105.4 linkuse as main transcript	c.43G>C	p.Gly15Arg	missense_variant	1/6		XP_011520407.1
APH1B	XR_007064490.1 linkuse as main transcript	n.62G>C		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APH1B	ENST00000261879.10 linkuse as main transcript	c.43G>C	p.Gly15Arg	missense_variant	1/6	1	NM_031301.4	ENSP00000261879.5		Q8WW43-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456210

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724634

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

The c.43G>C (p.G15R) alteration is located in exon 1 (coding exon 1) of the APH1B gene. This alteration results from a G to C substitution at nucleotide position 43, causing the glycine (G) at amino acid position 15 to be replaced by an arginine (R). 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

D;.;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Uncertain

-0.071

MutationAssessor

Uncertain

2.9

M;M;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.1

D;D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.93

MutPred

0.94

Gain of methylation at G15 (P = 0.0378);Gain of methylation at G15 (P = 0.0378);Gain of methylation at G15 (P = 0.0378);

MVP

0.82

MPC

0.36

ClinPred

1.0

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.85

gMVP

0.98

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over