NM_017439.4:c.577-19_577-11delTTTTTTTTT

Variant names:

• chr7-77377400-CAAAAAAAAA-C
• rs56314229
• NM_017439.4:c.577-19_577-11delTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_017439.4(GSAP):​c.577-19_577-11delTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,086,194 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 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSAP NM_017439.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.577-19_577-11delTTTTTTTTT		intron	N/A	NP_059135.2
	GSAP	NM_001350896.2		c.577-19_577-11delTTTTTTTTT		intron	N/A	NP_001337825.1
	GSAP	NM_001350897.2		c.577-19_577-11delTTTTTTTTT		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.577-19_577-11delTTTTTTTTT		intron	N/A	ENSP00000257626.7
	GSAP	ENST00000943097.1		c.577-19_577-11delTTTTTTTTT		intron	N/A	ENSP00000613156.1
	GSAP	ENST00000880888.1		c.577-19_577-11delTTTTTTTTT		intron	N/A	ENSP00000550947.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000133 AC: 145 AN: 1086194 Hom.: 0 AF XY: 0.000157 AC XY: 84 AN XY: 534424

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000436 AC: 1 AN: 22958

American (AMR) AF: 0.000335 AC: 7 AN: 20902

Ashkenazi Jewish (ASJ) AF: 0.000402 AC: 6 AN: 14916

East Asian (EAS) AF: 0.0000416 AC: 1 AN: 24036

South Asian (SAS) AF: 0.000324 AC: 17 AN: 52456

European-Finnish (FIN) AF: 0.000290 AC: 7 AN: 24148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3056

European-Non Finnish (NFE) AF: 0.000114 AC: 100 AN: 881052

Other (OTH) AF: 0.000141 AC: 6 AN: 42670

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 98072 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 45110

African (AFR) AF: 0.00 AC: 0 AN: 24902

American (AMR) AF: 0.00 AC: 0 AN: 8258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2670

East Asian (EAS) AF: 0.00 AC: 0 AN: 3160

South Asian (SAS) AF: 0.00 AC: 0 AN: 2948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 176

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51076

Other (OTH) AF: 0.00 AC: 0 AN: 1272

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

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;