Genetic Variant GSAP:c.577-11dupT (chr7-77377400-C-CA) – 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.577-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.098 ( 641 hom., cov: 0)

Exomes 𝑓: 0.026 ( 12 hom. )

Failed GnomAD Quality Control

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 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSAP	NM_017439.4 link	c.577-11dupT		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.577-11_577-10insT		intron_variant	Intron 8 of 30	1	NM_017439.4	ENSP00000257626.7		A4D1B5-1
GSAP	ENST00000334003.11 link	n.468-11_468-10insT		intron_variant	Intron 7 of 18	2

Frequencies

GnomAD3 genomes

AF:

0.0978

AC:

9566

AN:

97774

Hom.:

642

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.00606

Gnomad AMR

AF:

0.0975

Gnomad ASJ

AF:

0.0678

Gnomad EAS

AF:

0.350

Gnomad SAS

AF:

0.0762

Gnomad FIN

AF:

0.0671

Gnomad MID

AF:

0.0977

Gnomad NFE

AF:

0.0587

Gnomad OTH

AF:

0.0990

GnomAD4 exome

AF:

0.0262

AC:

28121

AN:

1072836

Hom.:

Cov.:

AF XY:

0.0255

AC XY:

13477

AN XY:

528232

show subpopulations

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

African (AFR)

AF:

0.0593

AC:

1324

AN:

22326

American (AMR)

AF:

0.0279

AC:

577

AN:

20704

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

261

AN:

14810

East Asian (EAS)

AF:

0.0961

AC:

2251

AN:

23412

South Asian (SAS)

AF:

0.0196

AC:

1024

AN:

52114

European-Finnish (FIN)

AF:

0.0199

AC:

477

AN:

23992

Middle Eastern (MID)

AF:

0.0286

AC:

AN:

3010

European-Non Finnish (NFE)

AF:

0.0239

AC:

20820

AN:

870430

Other (OTH)

AF:

0.0309

AC:

1301

AN:

42038

⚠️ 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: 0.327

Heterozygous variant carriers

1761

3522

5283

7044

8805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1032

2064

3096

4128

5160

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0978

AC:

9565

AN:

97778

Hom.:

641

Cov.:

AF XY:

0.0961

AC XY:

4324

AN XY:

45002

show subpopulations

African (AFR)

AF:

0.158

AC:

3931

AN:

24826

American (AMR)

AF:

0.0979

AC:

804

AN:

8214

Ashkenazi Jewish (ASJ)

AF:

0.0678

AC:

181

AN:

2670

East Asian (EAS)

AF:

0.350

AC:

1090

AN:

3116

South Asian (SAS)

AF:

0.0768

AC:

225

AN:

2928

European-Finnish (FIN)

AF:

0.0671

AC:

196

AN:

2920

Middle Eastern (MID)

AF:

0.104

AC:

AN:

164

European-Non Finnish (NFE)

AF:

0.0587

AC:

2993

AN:

51018

Other (OTH)

AF:

0.0983

AC:

124

AN:

1262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

363

725

1088

1450

1813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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 (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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7-77377400-CAAAAAAAAAAAAA-CAAAAAAAAAAAAAA

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