Genetic Variant GSAP:c.577-15_577-11delTTTTT (chr7-77377400-CAAAAA-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_017439.4(GSAP):c.577-15_577-11delTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,169,796 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 0)

Exomes 𝑓: 0.019 ( 5 hom. )

Consequence

GSAP
NM_017439.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

Publications

0 publications found

Variant links:

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]

GSAP links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GSAP	NM_017439.4	MANE Select	c.577-15_577-11delTTTTT	intron	N/A	NP_059135.2	A4D1B5-1
GSAP	NM_001350896.2		c.577-15_577-11delTTTTT	intron	N/A	NP_001337825.1
GSAP	NM_001350897.2		c.577-15_577-11delTTTTT	intron	N/A	NP_001337826.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GSAP	ENST00000257626.12	TSL:1 MANE Select	c.577-15_577-11delTTTTT	intron	N/A	ENSP00000257626.7	A4D1B5-1
GSAP	ENST00000943097.1		c.577-15_577-11delTTTTT	intron	N/A	ENSP00000613156.1
GSAP	ENST00000880888.1		c.577-15_577-11delTTTTT	intron	N/A	ENSP00000550947.1

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

128

AN:

98072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000727

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000316

Gnomad SAS

AF:

0.00102

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000861

Gnomad OTH

AF:

0.000786

GnomAD2 exomes

AF:

0.0670

AC:

6387

AN:

95370

AF XY:

0.0685

show subpopulations

Gnomad AFR exome

AF:

0.0926

Gnomad AMR exome

AF:

0.0642

Gnomad ASJ exome

AF:

0.0729

Gnomad EAS exome

AF:

0.0482

Gnomad FIN exome

AF:

0.0630

Gnomad NFE exome

AF:

0.0634

Gnomad OTH exome

AF:

0.0488

GnomAD4 exome

AF:

0.0194

AC:

20805

AN:

1071720

Hom.:

AF XY:

0.0209

AC XY:

10987

AN XY:

526952

show subpopulations

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

African (AFR)

AF:

0.0384

AC:

868

AN:

22576

American (AMR)

AF:

0.0506

AC:

1034

AN:

20438

Ashkenazi Jewish (ASJ)

AF:

0.0286

AC:

420

AN:

14660

East Asian (EAS)

AF:

0.0216

AC:

512

AN:

23734

South Asian (SAS)

AF:

0.0451

AC:

2329

AN:

51698

European-Finnish (FIN)

AF:

0.0274

AC:

653

AN:

23840

Middle Eastern (MID)

AF:

0.0352

AC:

106

AN:

3012

European-Non Finnish (NFE)

AF:

0.0160

AC:

13948

AN:

869688

Other (OTH)

AF:

0.0222

AC:

935

AN:

42074

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.309

Heterozygous variant carriers

1471

2942

4413

5884

7355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

424

848

1272

1696

2120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00133

AC:

130

AN:

98076

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

AN XY:

45128

show subpopulations

African (AFR)

AF:

0.00301

AC:

AN:

24942

American (AMR)

AF:

0.000727

AC:

AN:

8258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2670

East Asian (EAS)

AF:

0.000317

AC:

AN:

3150

South Asian (SAS)

AF:

0.00102

AC:

AN:

2936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.000862

AC:

AN:

51072

Other (OTH)

AF:

0.000786

AC:

AN:

1272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over