chr7-77377400-CAAAAAA-C

Variant names:

• chr7-77377400-CAAAAAA-C
• rs56314229
• NM_017439.4:c.577-16_577-11delTTTTTT

Variant summary

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

The NM_017439.4(GSAP):​c.577-16_577-11delTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0815 in 1,176,240 control chromosomes in the GnomAD database, including 493 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.081 (272 hom., cov: 0)
  • Exomes 𝑓: 0.082 (221 hom.)
• 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 (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSAP	NM_017439.4	c.577-16_577-11delTTTTTT		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.577-16_577-11delTTTTTT		intron_variant	Intron 8 of 30	1	NM_017439.4	ENSP00000257626.7
GSAP	ENST00000334003.11	n.468-16_468-11delTTTTTT		intron_variant	Intron 7 of 18	2

Frequencies

GnomAD3 genomes AF: 0.0807 AC: 7926 AN: 98226 Hom.: 272 Cov.: 0

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00909

Gnomad AMR AF: 0.0765

Gnomad ASJ AF: 0.0707

Gnomad EAS AF: 0.0275

Gnomad SAS AF: 0.0700

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.0227

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.0807

GnomAD3 exomes AF: 0.0798 AC: 7614 AN: 95370 Hom.: 25 AF XY: 0.0825 AC XY: 4376 AN XY: 53048

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.0492

Gnomad ASJ exome AF: 0.0706

Gnomad EAS exome AF: 0.0280

Gnomad SAS exome AF: 0.0642

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.0957

Gnomad OTH exome AF: 0.0914

GnomAD4 exome AF: 0.0816 AC: 87962 AN: 1078012 Hom.: 221 AF XY: 0.0818 AC XY: 43364 AN XY: 530348

Gnomad4 AFR exome AF: 0.0179

Gnomad4 AMR exome AF: 0.0502

Gnomad4 ASJ exome AF: 0.0653

Gnomad4 EAS exome AF: 0.0294

Gnomad4 SAS exome AF: 0.0546

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.0861

Gnomad4 OTH exome AF: 0.0741

GnomAD4 genome AF: 0.0807 AC: 7924 AN: 98228 Hom.: 272 Cov.: 0 AF XY: 0.0822 AC XY: 3714 AN XY: 45196

Gnomad4 AFR AF: 0.0216

Gnomad4 AMR AF: 0.0765

Gnomad4 ASJ AF: 0.0707

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.0700

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.0799

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;