rs4727380

Positions:

• chr7-77416489-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The XM_047420490.1(GSAP):​c.-537+25C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 416,368 control chromosomes in the GnomAD database, including 86,751 homozygotes. 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: 𝑓 0.66 (33524 hom., cov: 34)
  • Exomes 𝑓: 0.63 (53227 hom.)
• Consequence: GSAP XM_047420490.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0560

Genes affected

GSAP (HGNC:28042): (gamma-secretase activating protein) Accumulation of neurotoxic amyloid-beta is a major hallmark of Alzheimer disease (AD; MIM 104300). Formation of amyloid-beta is catalyzed by gamma-secretase (see PSEN1; MIM 104311), a protease with numerous substrates. PION, or GSAP, selectively increases amyloid-beta production through a mechanism involving its interaction with both gamma-secretase and its substrate, the amyloid-beta precursor protein (APP; MIM 104760) C-terminal fragment (APP-CTF) (He et al., 2010 [PubMed 20811458]).[supplied by OMIM, Nov 2010]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSAP	XM_047420490.1	c.-537+25C>G		intron_variant			XP_047276446.1
GSAP	XM_047420491.1	c.-537+124C>G		intron_variant			XP_047276447.1
GSAP	XM_047420493.1	c.-537+25C>G		intron_variant			XP_047276449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100532 AN: 151930 Hom.: 33474 Cov.: 34

Gnomad AFR AF: 0.723

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.631

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.631

GnomAD4 exome AF: 0.632 AC: 167105 AN: 264332 Hom.: 53227 Cov.: 3 AF XY: 0.628 AC XY: 86505 AN XY: 137700

Gnomad4 AFR exome AF: 0.723

Gnomad4 AMR exome AF: 0.663

Gnomad4 ASJ exome AF: 0.632

Gnomad4 EAS exome AF: 0.626

Gnomad4 SAS exome AF: 0.479

Gnomad4 FIN exome AF: 0.627

Gnomad4 NFE exome AF: 0.640

Gnomad4 OTH exome AF: 0.632

GnomAD4 genome AF: 0.662 AC: 100628 AN: 152036 Hom.: 33524 Cov.: 34 AF XY: 0.658 AC XY: 48916 AN XY: 74320

Gnomad4 AFR AF: 0.723

Gnomad4 AMR AF: 0.673

Gnomad4 ASJ AF: 0.631

Gnomad4 EAS AF: 0.658

Gnomad4 SAS AF: 0.446

Gnomad4 FIN AF: 0.636

Gnomad4 NFE AF: 0.644

Gnomad4 OTH AF: 0.627

Alfa AF: 0.650 Hom.: 4001

Bravo AF: 0.670

Asia WGS AF: 0.515 AC: 1782 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.67

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4727380; hg19: chr7-77045806;