7-77377400-CAAAAAAAAAAAA-CAAAA

Position:

• chr7-77377400-CAAAAAAAAAAAA-CAAAA

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017439.4(GSAP):​c.577-18_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 0.00122 in 1,183,156 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: GSAP NM_017439.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSAP	NM_017439.4	c.577-18_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.577-18_577-11del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_017439.4	ENSP00000257626	P1
GSAP	ENST00000334003.11	n.468-18_468-11del		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000612 AC: 6 AN: 98072 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000979

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00133 AC: 1439 AN: 1085084 Hom.: 0 AF XY: 0.00148 AC XY: 789 AN XY: 533888

Gnomad4 AFR exome AF: 0.000480

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.00208

Gnomad4 EAS exome AF: 0.000916

Gnomad4 SAS exome AF: 0.00225

Gnomad4 FIN exome AF: 0.00456

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.00183

GnomAD4 genome AF: 0.0000612 AC: 6 AN: 98072 Hom.: 0 Cov.: 0 AF XY: 0.0000887 AC XY: 4 AN XY: 45110

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000339

Gnomad4 NFE AF: 0.0000979

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;