Genetic Variant GSAP:c.577-11delT (chr7-77377400-CA-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.577-11delT 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 0.070 ( 155 hom., cov: 0)

Exomes 𝑓: 0.078 ( 55 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 55 AR gene

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.577-11delT	intron	N/A	NP_059135.2	A4D1B5-1
GSAP	NM_001350896.2		c.577-11delT	intron	N/A	NP_001337825.1
GSAP	NM_001350897.2		c.577-11delT	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.577-11delT	intron	N/A	ENSP00000257626.7	A4D1B5-1
GSAP	ENST00000943097.1		c.577-11delT	intron	N/A	ENSP00000613156.1
GSAP	ENST00000880888.1		c.577-11delT	intron	N/A	ENSP00000550947.1

Frequencies

GnomAD3 genomes

AF:

0.0702

AC:

6875

AN:

97984

Hom.:

154

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0536

Gnomad AMI

AF:

0.0106

Gnomad AMR

AF:

0.0485

Gnomad ASJ

AF:

0.145

Gnomad EAS

AF:

0.00633

Gnomad SAS

AF:

0.0669

Gnomad FIN

AF:

0.0861

Gnomad MID

AF:

0.0966

Gnomad NFE

AF:

0.0819

Gnomad OTH

AF:

0.0623

GnomAD4 exome

AF:

0.0781

AC:

82741

AN:

1059568

Hom.:

Cov.:

AF XY:

0.0761

AC XY:

39703

AN XY:

521660

show subpopulations

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

African (AFR)

AF:

0.0516

AC:

1161

AN:

22494

American (AMR)

AF:

0.0320

AC:

659

AN:

20564

Ashkenazi Jewish (ASJ)

AF:

0.0886

AC:

1287

AN:

14520

East Asian (EAS)

AF:

0.0486

AC:

1152

AN:

23690

South Asian (SAS)

AF:

0.0486

AC:

2505

AN:

51586

European-Finnish (FIN)

AF:

0.0724

AC:

1708

AN:

23602

Middle Eastern (MID)

AF:

0.0711

AC:

212

AN:

2982

European-Non Finnish (NFE)

AF:

0.0826

AC:

70893

AN:

858460

Other (OTH)

AF:

0.0759

AC:

3164

AN:

41670

⚠️ 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: 0.326

Heterozygous variant carriers

5265

10530

15796

21061

26326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3196

6392

9588

12784

15980

<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:

0.0701

AC:

6872

AN:

97988

Hom.:

155

Cov.:

AF XY:

0.0690

AC XY:

3110

AN XY:

45084

show subpopulations

African (AFR)

AF:

0.0536

AC:

1337

AN:

24932

American (AMR)

AF:

0.0485

AC:

400

AN:

8248

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

387

AN:

2664

East Asian (EAS)

AF:

0.00635

AC:

AN:

3148

South Asian (SAS)

AF:

0.0665

AC:

195

AN:

2932

European-Finnish (FIN)

AF:

0.0861

AC:

253

AN:

2938

Middle Eastern (MID)

AF:

0.0904

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.0819

AC:

4181

AN:

51032

Other (OTH)

AF:

0.0607

AC:

AN:

1268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

248

496

745

993

1241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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

(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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chr7-77377401-AAAAAAA-AAAAAA

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