chr7-77377400-CAA-C

Variant names:

• chr7-77377400-CAA-C
• rs56314229
• NM_017439.4:c.577-12_577-11delTT

Variant summary

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

The NM_017439.4(GSAP):​c.577-12_577-11delTT variant causes a 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 0.37 (5216 hom., cov: 0)
  • Exomes 𝑓: 0.28 (1281 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSAP NM_017439.4 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 (AMR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSAP	NM_017439.4	c.577-12_577-11delTT		intron_variant	Intron 8 of 30	ENST00000257626.12	NP_059135.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSAP	ENST00000257626.12	c.577-12_577-11delTT		intron_variant	Intron 8 of 30	1	NM_017439.4	ENSP00000257626.7
GSAP	ENST00000334003.11	n.468-12_468-11delTT		intron_variant	Intron 7 of 18	2

Frequencies

GnomAD3 genomes AF: 0.371 AC: 36368 AN: 98066 Hom.: 5218 Cov.: 0

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.386

GnomAD3 exomes AF: 0.126 AC: 12043 AN: 95370 Hom.: 86 AF XY: 0.121 AC XY: 6394 AN XY: 53048

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.0703

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.139

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.279 AC: 292972 AN: 1048728 Hom.: 1281 AF XY: 0.273 AC XY: 140990 AN XY: 516154

Gnomad4 AFR exome AF: 0.217

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.245

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.186

Gnomad4 NFE exome AF: 0.295

Gnomad4 OTH exome AF: 0.267

GnomAD4 genome AF: 0.371 AC: 36353 AN: 98070 Hom.: 5216 Cov.: 0 AF XY: 0.365 AC XY: 16458 AN XY: 45060

Gnomad4 AFR AF: 0.309

Gnomad4 AMR AF: 0.413

Gnomad4 ASJ AF: 0.359

Gnomad4 EAS AF: 0.368

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.324

Gnomad4 NFE AF: 0.397

Gnomad4 OTH AF: 0.386

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;