7-77377400-CAAAAAAAAAAAAA-CAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017439.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSAP	NM_017439.4	MANE Select	c.577-16_577-11delTTTTTT		intron	N/A	NP_059135.2	A4D1B5-1
	GSAP	NM_001350896.2		c.577-16_577-11delTTTTTT		intron	N/A	NP_001337825.1
	GSAP	NM_001350897.2		c.577-16_577-11delTTTTTT		intron	N/A	NP_001337826.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSAP	ENST00000257626.12	TSL:1 MANE Select	c.577-16_577-11delTTTTTT		intron	N/A	ENSP00000257626.7	A4D1B5-1
	GSAP	ENST00000943097.1		c.577-16_577-11delTTTTTT		intron	N/A	ENSP00000613156.1
	GSAP	ENST00000880888.1		c.577-16_577-11delTTTTTT		intron	N/A	ENSP00000550947.1

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

GnomAD2 exomes AF: 0.0798 AC: 7614 AN: 95370 AF XY: 0.0825

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 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

African (AFR) AF: 0.0179 AC: 409 AN: 22798

American (AMR) AF: 0.0502 AC: 1038 AN: 20660

Ashkenazi Jewish (ASJ) AF: 0.0653 AC: 968 AN: 14828

East Asian (EAS) AF: 0.0294 AC: 702 AN: 23868

South Asian (SAS) AF: 0.0546 AC: 2839 AN: 51994

European-Finnish (FIN) AF: 0.144 AC: 3460 AN: 23954

Middle Eastern (MID) AF: 0.0435 AC: 132 AN: 3034

European-Non Finnish (NFE) AF: 0.0861 AC: 75277 AN: 874546

Other (OTH) AF: 0.0741 AC: 3137 AN: 42330

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

African (AFR) AF: 0.0216 AC: 538 AN: 24944

American (AMR) AF: 0.0765 AC: 632 AN: 8264

Ashkenazi Jewish (ASJ) AF: 0.0707 AC: 189 AN: 2674

East Asian (EAS) AF: 0.0276 AC: 87 AN: 3148

South Asian (SAS) AF: 0.0700 AC: 206 AN: 2944

European-Finnish (FIN) AF: 0.232 AC: 688 AN: 2964

Middle Eastern (MID) AF: 0.0241 AC: 4 AN: 166

European-Non Finnish (NFE) AF: 0.107 AC: 5472 AN: 51188

Other (OTH) AF: 0.0799 AC: 102 AN: 1276

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56314229; hg19: chr7-77006717;