Genetic Variant NM_017439.4:c.577-12_577-11delTT (chr7-77377400-CAA-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.577-12_577-11delTT 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 0.37 ( 5216 hom., cov: 0)

Exomes 𝑓: 0.28 ( 1281 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: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.371

AC:

36368

AN:

98066

Hom.:

5218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.310

Gnomad AMI

AF:

0.562

Gnomad AMR

AF:

0.414

Gnomad ASJ

AF:

0.359

Gnomad EAS

AF:

0.368

Gnomad SAS

AF:

0.320

Gnomad FIN

AF:

0.324

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.397

Gnomad OTH

AF:

0.386

GnomAD2 exomes

AF:

0.126

AC:

12043

AN:

95370

AF XY:

0.121

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.160

Gnomad ASJ exome

AF:

0.126

Gnomad EAS exome

AF:

0.152

Gnomad FIN exome

AF:

0.0703

Gnomad NFE exome

AF:

0.128

Gnomad OTH exome

AF:

0.139

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.279

AC:

292972

AN:

1048728

Hom.:

1281

AF XY:

0.273

AC XY:

140990

AN XY:

516154

show subpopulations

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

African (AFR)

AF:

0.217

AC:

4862

AN:

22364

American (AMR)

AF:

0.179

AC:

3637

AN:

20322

Ashkenazi Jewish (ASJ)

AF:

0.245

AC:

3557

AN:

14496

East Asian (EAS)

AF:

0.226

AC:

5287

AN:

23386

South Asian (SAS)

AF:

0.169

AC:

8679

AN:

51340

European-Finnish (FIN)

AF:

0.186

AC:

4339

AN:

23282

Middle Eastern (MID)

AF:

0.244

AC:

729

AN:

2984

European-Non Finnish (NFE)

AF:

0.295

AC:

250850

AN:

849250

Other (OTH)

AF:

0.267

AC:

11032

AN:

41304

⚠️ 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: 0.389

Heterozygous variant carriers

11469

22939

34408

45878

57347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11198

22396

33594

44792

55990

<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:

0.371

AC:

36353

AN:

98070

Hom.:

5216

Cov.:

AF XY:

0.365

AC XY:

16458

AN XY:

45060

show subpopulations

African (AFR)

AF:

0.309

AC:

7719

AN:

24948

American (AMR)

AF:

0.413

AC:

3413

AN:

8256

Ashkenazi Jewish (ASJ)

AF:

0.359

AC:

959

AN:

2674

East Asian (EAS)

AF:

0.368

AC:

1158

AN:

3148

South Asian (SAS)

AF:

0.321

AC:

944

AN:

2944

European-Finnish (FIN)

AF:

0.324

AC:

948

AN:

2922

Middle Eastern (MID)

AF:

0.399

AC:

AN:

168

European-Non Finnish (NFE)

AF:

0.397

AC:

20283

AN:

51076

Other (OTH)

AF:

0.386

AC:

492

AN:

1276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

984

1968

2952

3936

4920

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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)

0.0

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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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