15-63305658-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.049 (272 hom., cov: 33)
  • Exomes 𝑓: 0.040 (2169 hom.)
• Consequence: APH1B NM_031301.4 missense
• 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: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APH1B	NM_031301.4	MANE Select	c.651T>G	p.Phe217Leu	missense	Exon 6 of 6	NP_112591.2
	APH1B	NM_001145646.2		c.528T>G	p.Phe176Leu	missense	Exon 5 of 5	NP_001139118.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APH1B	ENST00000261879.10	TSL:1 MANE Select	c.651T>G	p.Phe217Leu	missense	Exon 6 of 6	ENSP00000261879.5
	APH1B	ENST00000380343.8	TSL:1	c.528T>G	p.Phe176Leu	missense	Exon 5 of 5	ENSP00000369700.4
	APH1B	ENST00000559971.5	TSL:1	n.*727T>G		non_coding_transcript_exon	Exon 6 of 6	ENSP00000453516.1

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 7441 AN: 152202 Hom.: 274 Cov.: 33

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

GnomAD2 exomes AF: 0.0605 AC: 15196 AN: 251078 AF XY: 0.0572

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 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.: 31 AF XY: 0.0404 AC XY: 29346 AN XY: 727216

African (AFR) AF: 0.0584 AC: 1956 AN: 33480

American (AMR) AF: 0.139 AC: 6204 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0477 AC: 1247 AN: 26134

East Asian (EAS) AF: 0.197 AC: 7828 AN: 39694

South Asian (SAS) AF: 0.0481 AC: 4149 AN: 86256

European-Finnish (FIN) AF: 0.0303 AC: 1617 AN: 53420

Middle Eastern (MID) AF: 0.0713 AC: 411 AN: 5766

European-Non Finnish (NFE) AF: 0.0294 AC: 32690 AN: 1111982

Other (OTH) AF: 0.0482 AC: 2913 AN: 60394

GnomAD4 genome AF: 0.0489 AC: 7450 AN: 152320 Hom.: 272 Cov.: 33 AF XY: 0.0496 AC XY: 3692 AN XY: 74476

African (AFR) AF: 0.0571 AC: 2372 AN: 41574

American (AMR) AF: 0.0891 AC: 1363 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3470

East Asian (EAS) AF: 0.174 AC: 902 AN: 5172

South Asian (SAS) AF: 0.0495 AC: 239 AN: 4828

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0298 AC: 2025 AN: 68034

Other (OTH) AF: 0.0553 AC: 117 AN: 2114

Alfa AF: 0.0379 Hom.: 248

Bravo AF: 0.0568

TwinsUK AF: 0.0275 AC: 102

ALSPAC AF: 0.0254 AC: 98

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.041
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.068
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.047	B
Vest4		0.072
MutPred		0.50		Loss of glycosylation at S215 (P = 0.2232)
MPC		0.072
ClinPred		0.042	T
GERP RS		0.014
Varity_R		0.23
gMVP		0.59
Mutation Taster		=94/6	polymorphism (auto)

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; COSMIC: COSV56013914; COSMIC: COSV56013914;