Genetic Variant GSAP: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

new If you want to explore the variant's impact on the transcript NM_017439.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017439.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GSAP	NM_017439.4	MANE Select	c.577-12_577-11delTT	intron	N/A	NP_059135.2	A4D1B5-1
GSAP	NM_001350896.2		c.577-12_577-11delTT	intron	N/A	NP_001337825.1
GSAP	NM_001350897.2		c.577-12_577-11delTT	intron	N/A	NP_001337826.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GSAP	ENST00000257626.12	TSL:1 MANE Select	c.577-12_577-11delTT	intron	N/A	ENSP00000257626.7	A4D1B5-1
GSAP	ENST00000943097.1		c.577-12_577-11delTT	intron	N/A	ENSP00000613156.1
GSAP	ENST00000880888.1		c.577-12_577-11delTT	intron	N/A	ENSP00000550947.1

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), 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 v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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7-77377400-CAAAAAAAAAAAAA-CAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over