7-77377400-CAAAAAAAAAAAA-CAAAAA

Position:

• chr7-77377400-CAAAAAAAAAAAA-CAAAAA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_017439.4(GSAP):​c.577-17_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 0.0111 in 1,180,672 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.012 (2 hom.)
• Consequence: GSAP NM_017439.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.473

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSAP	NM_017439.4	c.577-17_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.577-17_577-11del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_017439.4	ENSP00000257626	P1
GSAP	ENST00000334003.11	n.468-17_468-11del		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 137 AN: 98070 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000643

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000605

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000316

Gnomad SAS AF: 0.000678

Gnomad FIN AF: 0.00102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0248 AC: 2367 AN: 95370 Hom.: 3 AF XY: 0.0261 AC XY: 1383 AN XY: 53048

Gnomad AFR exome AF: 0.00811

Gnomad AMR exome AF: 0.00884

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.00780

Gnomad SAS exome AF: 0.0207

Gnomad FIN exome AF: 0.0581

Gnomad NFE exome AF: 0.0306

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0120 AC: 12993 AN: 1082598 Hom.: 2 AF XY: 0.0126 AC XY: 6689 AN XY: 532548

Gnomad4 AFR exome AF: 0.00314

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.00625

Gnomad4 SAS exome AF: 0.0125

Gnomad4 FIN exome AF: 0.0329

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.00140 AC: 137 AN: 98074 Hom.: 0 Cov.: 0 AF XY: 0.00155 AC XY: 70 AN XY: 45128

Gnomad4 AFR AF: 0.000641

Gnomad4 AMR AF: 0.000605

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000317

Gnomad4 SAS AF: 0.000681

Gnomad4 FIN AF: 0.00102

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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;