7-77377400-CAAAAAAAAAAAA-CAAAAAAAA

Position:

• chr7-77377400-CAAAAAAAAAAAA-CAAAAAAAA

Variant summary

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

The NM_017439.4(GSAP):​c.577-14_577-11del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0668 in 1,152,898 control chromosomes in the GnomAD database, including 48 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (23 hom., cov: 0)
  • Exomes 𝑓: 0.072 (25 hom.)
• 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: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSAP	NM_017439.4	c.577-14_577-11del		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.577-14_577-11del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_017439.4	ENSP00000257626	P1
GSAP	ENST00000334003.11	n.468-14_468-11del		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 1613 AN: 98090 Hom.: 23 Cov.: 0

Gnomad AFR AF: 0.0535

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00187

Gnomad EAS AF: 0.000949

Gnomad SAS AF: 0.00543

Gnomad FIN AF: 0.000678

Gnomad MID AF: 0.00568

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.0142

GnomAD3 exomes AF: 0.147 AC: 14006 AN: 95370 Hom.: 17 AF XY: 0.152 AC XY: 8063 AN XY: 53048

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.106

Gnomad SAS exome AF: 0.160

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.0715 AC: 75439 AN: 1054804 Hom.: 25 AF XY: 0.0735 AC XY: 38149 AN XY: 518948

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.0966

Gnomad4 EAS exome AF: 0.0733

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0730

Gnomad4 NFE exome AF: 0.0650

Gnomad4 OTH exome AF: 0.0830

GnomAD4 genome AF: 0.0165 AC: 1619 AN: 98094 Hom.: 23 Cov.: 0 AF XY: 0.0169 AC XY: 762 AN XY: 45136

Gnomad4 AFR AF: 0.0536

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00187

Gnomad4 EAS AF: 0.000952

Gnomad4 SAS AF: 0.00545

Gnomad4 FIN AF: 0.000678

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.0149

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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: rs56314229; hg19: chr7-77006717;