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

Transcripts

RefSeq

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

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 = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.326

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 v4.3

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

Publications

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7-77377400-CAAAAAAAAAAAAA-CAAAAAAAAAAAA

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