Genetic Variant NM_017439.4:c.577-14_577-11delTTTT (chr7-77377400-CAAAA-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.577-14_577-11delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0668 in 1,152,898 control chromosomes in the GnomAD database, including 48 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.017 ( 23 hom., cov: 0)

Exomes 𝑓: 0.072 ( 25 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 (AFR) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSAP	NM_017439.4 link	c.577-14_577-11delTTTT		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.577-14_577-11delTTTT		intron_variant	Intron 8 of 30	1	NM_017439.4	ENSP00000257626.7		A4D1B5-1
GSAP	ENST00000334003.11 link	n.468-14_468-11delTTTT		intron_variant	Intron 7 of 18	2

Frequencies

GnomAD3 genomes

AF:

0.0164

AC:

1613

AN:

98090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0535

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0105

Gnomad ASJ

AF:

0.00187

Gnomad EAS

AF:

0.000949

Gnomad SAS

AF:

0.00543

Gnomad FIN

AF:

0.000678

Gnomad MID

AF:

0.00568

Gnomad NFE

AF:

0.00288

Gnomad OTH

AF:

0.0142

GnomAD2 exomes

AF:

0.147

AC:

14006

AN:

95370

AF XY:

0.152

show subpopulations

Gnomad AFR exome

AF:

0.185

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.106

Gnomad FIN exome

AF:

0.125

Gnomad NFE exome

AF:

0.148

Gnomad OTH exome

AF:

0.127

GnomAD4 exome

AF:

0.0715

AC:

75439

AN:

1054804

Hom.:

AF XY:

0.0735

AC XY:

38149

AN XY:

518948

show subpopulations

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

African (AFR)

AF:

0.133

AC:

2964

AN:

22286

American (AMR)

AF:

0.123

AC:

2505

AN:

20294

Ashkenazi Jewish (ASJ)

AF:

0.0966

AC:

1403

AN:

14524

East Asian (EAS)

AF:

0.0733

AC:

1723

AN:

23504

South Asian (SAS)

AF:

0.114

AC:

5821

AN:

51234

European-Finnish (FIN)

AF:

0.0730

AC:

1727

AN:

23664

Middle Eastern (MID)

AF:

0.0948

AC:

282

AN:

2974

European-Non Finnish (NFE)

AF:

0.0650

AC:

55569

AN:

854814

Other (OTH)

AF:

0.0830

AC:

3445

AN:

41510

⚠️ 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: 0.327

Heterozygous variant carriers

4687

9375

14062

18750

23437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2060

4120

6180

8240

10300

<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:

0.0165

AC:

1619

AN:

98094

Hom.:

Cov.:

AF XY:

0.0169

AC XY:

762

AN XY:

45136

show subpopulations

African (AFR)

AF:

0.0536

AC:

1339

AN:

24964

American (AMR)

AF:

0.0105

AC:

AN:

8258

Ashkenazi Jewish (ASJ)

AF:

0.00187

AC:

AN:

2670

East Asian (EAS)

AF:

0.000952

AC:

AN:

3150

South Asian (SAS)

AF:

0.00545

AC:

AN:

2936

European-Finnish (FIN)

AF:

0.000678

AC:

AN:

2950

Middle Eastern (MID)

AF:

0.00602

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.00288

AC:

147

AN:

51068

Other (OTH)

AF:

0.0149

AC:

AN:

1272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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