chr15-63287541-A-G

Variant names:

• chr15-63287541-A-G
• rs201964174
• NM_031301.4:c.473A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031301.4(APH1B):​c.473A>G​(p.Tyr158Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y158F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APH1B NM_031301.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.21
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26892006).

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.473A>G	p.Tyr158Cys	missense	Exon 4 of 6	NP_112591.2	Q8WW43-1
	APH1B	NM_001145646.2		c.355+913A>G		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.473A>G	p.Tyr158Cys	missense	Exon 4 of 6	ENSP00000261879.5	Q8WW43-1
	APH1B	ENST00000380343.8	TSL:1	c.355+913A>G		intron	N/A	ENSP00000369700.4	Q8WW43-2
	APH1B	ENST00000559971.5	TSL:1	n.*549A>G		non_coding_transcript_exon	Exon 4 of 6	ENSP00000453516.1	H0YM95

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.14
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.010	D
Polyphen		0.76	P
Vest4		0.46
MutPred		0.45		Loss of helix (P = 0.028)
MVP		0.59
MPC		0.11
ClinPred		0.71	D
GERP RS		1.8
Varity_R		0.055
gMVP		0.32

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: rs201964174; hg19: chr15-63579740; COSMIC: COSV56014167; COSMIC: COSV56014167;