Genetic Variant NM_017439.4:c.577-16_577-11delTTTTTT (chr7-77377400-CAAAAAA-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_017439.4(GSAP):c.577-16_577-11delTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0815 in 1,176,240 control chromosomes in the GnomAD database, including 493 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.081 ( 272 hom., cov: 0)

Exomes 𝑓: 0.082 ( 221 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: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSAP	NM_017439.4 link	c.577-16_577-11delTTTTTT		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.577-16_577-11delTTTTTT		intron_variant	Intron 8 of 30	1	NM_017439.4	ENSP00000257626.7		A4D1B5-1
GSAP	ENST00000334003.11 link	n.468-16_468-11delTTTTTT		intron_variant	Intron 7 of 18	2

Frequencies

GnomAD3 genomes

AF:

0.0807

AC:

7926

AN:

98226

Hom.:

272

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0216

Gnomad AMI

AF:

0.00909

Gnomad AMR

AF:

0.0765

Gnomad ASJ

AF:

0.0707

Gnomad EAS

AF:

0.0275

Gnomad SAS

AF:

0.0700

Gnomad FIN

AF:

0.232

Gnomad MID

AF:

0.0227

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.0807

GnomAD2 exomes

AF:

0.0798

AC:

7614

AN:

95370

AF XY:

0.0825

show subpopulations

Gnomad AFR exome

AF:

0.0291

Gnomad AMR exome

AF:

0.0492

Gnomad ASJ exome

AF:

0.0706

Gnomad EAS exome

AF:

0.0280

Gnomad FIN exome

AF:

0.160

Gnomad NFE exome

AF:

0.0957

Gnomad OTH exome

AF:

0.0914

GnomAD4 exome

AF:

0.0816

AC:

87962

AN:

1078012

Hom.:

221

AF XY:

0.0818

AC XY:

43364

AN XY:

530348

show subpopulations

African (AFR)

AF:

0.0179

AC:

409

AN:

22798

American (AMR)

AF:

0.0502

AC:

1038

AN:

20660

Ashkenazi Jewish (ASJ)

AF:

0.0653

AC:

968

AN:

14828

East Asian (EAS)

AF:

0.0294

AC:

702

AN:

23868

South Asian (SAS)

AF:

0.0546

AC:

2839

AN:

51994

European-Finnish (FIN)

AF:

0.144

AC:

3460

AN:

23954

Middle Eastern (MID)

AF:

0.0435

AC:

132

AN:

3034

European-Non Finnish (NFE)

AF:

0.0861

AC:

75277

AN:

874546

Other (OTH)

AF:

0.0741

AC:

3137

AN:

42330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

3015

6031

9046

12062

15077

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3034

6068

9102

12136

15170

<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:

0.0807

AC:

7924

AN:

98228

Hom.:

272

Cov.:

AF XY:

0.0822

AC XY:

3714

AN XY:

45196

show subpopulations

African (AFR)

AF:

0.0216

AC:

538

AN:

24944

American (AMR)

AF:

0.0765

AC:

632

AN:

8264

Ashkenazi Jewish (ASJ)

AF:

0.0707

AC:

189

AN:

2674

East Asian (EAS)

AF:

0.0276

AC:

AN:

3148

South Asian (SAS)

AF:

0.0700

AC:

206

AN:

2944

European-Finnish (FIN)

AF:

0.232

AC:

688

AN:

2964

Middle Eastern (MID)

AF:

0.0241

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.107

AC:

5472

AN:

51188

Other (OTH)

AF:

0.0799

AC:

102

AN:

1276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

Heterozygous variant carriers

297

594

890

1187

1484

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over