rs2293452

chr7-77327322-G-A

Variant summary

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

The NM_017439.4(GSAP):c.1766-1049C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 152,346 control chromosomes in the GnomAD database, including 9,105 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 0.34 (9086 hom., cov: 32)
  • Exomes 𝑓: 0.32 (19 hom.)
• Consequence: GSAP NM_017439.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.132

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]

CCDC146 (HGNC:29296): (coiled-coil domain containing 146) Located in centriole. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSAP	NM_017439.4	c.1766-1049C>T		intron_variant		ENST00000257626.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSAP	ENST00000257626.12	c.1766-1049C>T		intron_variant		1	NM_017439.4	P1

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50971 AN: 151944 Hom.: 9054 Cov.: 32

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.307

GnomAD4 exome AF: 0.324 AC: 92 AN: 284 Hom.: 19 Cov.: 0 AF XY: 0.327 AC XY: 66 AN XY: 202

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.333

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.317

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.336 AC: 51056 AN: 152062 Hom.: 9086 Cov.: 32 AF XY: 0.338 AC XY: 25149 AN XY: 74340

Gnomad4 AFR AF: 0.432

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.249

Gnomad4 EAS AF: 0.474

Gnomad4 SAS AF: 0.363

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.315

Alfa AF: 0.284 Hom.: 8492

Bravo AF: 0.340

Asia WGS AF: 0.418 AC: 1452 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.7
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs2293452; hg19: chr7-76956639;