15-63305658-T-C

Variant names:

• chr15-63305658-T-C
• rs1047552
• NM_031301.4:c.651T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_031301.4(APH1B):​c.651T>C​(p.Phe217Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: APH1B NM_031301.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0410
• Publications: 27 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14569986).
• BP7: Synonymous conserved (PhyloP=-0.041 with no splicing effect.

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.651T>C	p.Phe217Phe	synonymous	Exon 6 of 6	NP_112591.2	Q8WW43-1
	APH1B	NM_001145646.2		c.528T>C	p.Phe176Phe	synonymous	Exon 5 of 5	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.651T>C	p.Phe217Phe	synonymous	Exon 6 of 6	ENSP00000261879.5	Q8WW43-1
	APH1B	ENST00000380343.8	TSL:1	c.528T>C	p.Phe176Phe	synonymous	Exon 5 of 5	ENSP00000369700.4	Q8WW43-2
	APH1B	ENST00000559971.5	TSL:1	n.*727T>C		non_coding_transcript_exon	Exon 6 of 6	ENSP00000453516.1	H0YM95

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.82
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.15	T
PhyloP100		-0.041
PROVEAN	Benign	-2.1	N
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
MVP		0.70
GERP RS		0.014

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: rs1047552; hg19: chr15-63597857;