7-77377400-CAAAAAAAAAAAA-CAAAAAAAAAAAAA

Position:

• chr7-77377400-CAAAAAAAAAAAA-CAAAAAAAAAAAAA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_017439.4(GSAP):​c.577-11_577-10insT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.098 (641 hom., cov: 0)
  • Exomes 𝑓: 0.026 (12 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSAP NM_017439.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSAP	NM_017439.4	c.577-11_577-10insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000257626.12	NP_059135.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSAP	ENST00000257626.12	c.577-11_577-10insT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_017439.4	ENSP00000257626	P1
GSAP	ENST00000334003.11	n.468-11_468-10insT		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 9566 AN: 97774 Hom.: 642 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00606

Gnomad AMR AF: 0.0975

Gnomad ASJ AF: 0.0678

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.0762

Gnomad FIN AF: 0.0671

Gnomad MID AF: 0.0977

Gnomad NFE AF: 0.0587

Gnomad OTH AF: 0.0990

GnomAD4 exome AF: 0.0262 AC: 28121 AN: 1072836 Hom.: 12 Cov.: 0 AF XY: 0.0255 AC XY: 13477 AN XY: 528232

Gnomad4 AFR exome AF: 0.0593

Gnomad4 AMR exome AF: 0.0279

Gnomad4 ASJ exome AF: 0.0176

Gnomad4 EAS exome AF: 0.0961

Gnomad4 SAS exome AF: 0.0196

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.0239

Gnomad4 OTH exome AF: 0.0309

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0978 AC: 9565 AN: 97778 Hom.: 641 Cov.: 0 AF XY: 0.0961 AC XY: 4324 AN XY: 45002

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.0979

Gnomad4 ASJ AF: 0.0678

Gnomad4 EAS AF: 0.350

Gnomad4 SAS AF: 0.0768

Gnomad4 FIN AF: 0.0671

Gnomad4 NFE AF: 0.0587

Gnomad4 OTH AF: 0.0983

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56314229; hg19: chr7-77006717;