Genetic Variant GSAP:c.577-17_577-11delTTTTTTT (chr7-77377400-CAAAAAAA-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.577-17_577-11delTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,180,672 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 0)

Exomes 𝑓: 0.012 ( 2 hom. )

Consequence

GSAP
NM_017439.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.473

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 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSAP	NM_017439.4 link	c.577-17_577-11delTTTTTTT		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.577-17_577-11delTTTTTTT		intron_variant	Intron 8 of 30	1	NM_017439.4	ENSP00000257626.7		A4D1B5-1
GSAP	ENST00000334003.11 link	n.468-17_468-11delTTTTTTT		intron_variant	Intron 7 of 18	2

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

137

AN:

98070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000643

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000605

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000316

Gnomad SAS

AF:

0.000678

Gnomad FIN

AF:

0.00102

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0248

AC:

2367

AN:

95370

AF XY:

0.0261

show subpopulations

Gnomad AFR exome

AF:

0.00811

Gnomad AMR exome

AF:

0.00884

Gnomad ASJ exome

AF:

0.0201

Gnomad EAS exome

AF:

0.00780

Gnomad FIN exome

AF:

0.0581

Gnomad NFE exome

AF:

0.0306

Gnomad OTH exome

AF:

0.0277

GnomAD4 exome

AF:

0.0120

AC:

12993

AN:

1082598

Hom.:

AF XY:

0.0126

AC XY:

6689

AN XY:

532548

show subpopulations

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

African (AFR)

AF:

0.00314

AC:

AN:

22906

American (AMR)

AF:

0.0102

AC:

213

AN:

20842

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

168

AN:

14852

East Asian (EAS)

AF:

0.00625

AC:

150

AN:

23992

South Asian (SAS)

AF:

0.0125

AC:

653

AN:

52250

European-Finnish (FIN)

AF:

0.0329

AC:

791

AN:

24042

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

3052

European-Non Finnish (NFE)

AF:

0.0118

AC:

10398

AN:

878112

Other (OTH)

AF:

0.0122

AC:

517

AN:

42550

⚠️ 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: 0.344

Heterozygous variant carriers

734

1468

2202

2936

3670

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.00140

AC:

137

AN:

98074

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

AN XY:

45128

show subpopulations

African (AFR)

AF:

0.000641

AC:

AN:

24942

American (AMR)

AF:

0.000605

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:

0.000681

AC:

AN:

2936

European-Finnish (FIN)

AF:

0.00102

AC:

AN:

2950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.00215

AC:

110

AN:

51070

Other (OTH)

AF:

0.00

AC:

AN:

1272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.571

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

0.47

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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7-77377400-CAAAAAAAAAAAAA-CAAAAAA

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