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:

Genome browser will be placed here

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSAP	NM_017439.4 link	c.577-15_577-11delTTTTT		intron_variant	Intron 8 of 30	ENST00000257626.12	NP_059135.2	A4D1B5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSAP	ENST00000257626.12 link	c.577-15_577-11delTTTTT		intron_variant	Intron 8 of 30	1	NM_017439.4	ENSP00000257626.7		A4D1B5-1
GSAP	ENST00000334003.11 link	n.468-15_468-11delTTTTT		intron_variant	Intron 7 of 18	2

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 = 0.000000), 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 v4.3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

7-77377400-CAAAAAAAAAAAAA-CAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over