Genetic Variant NM_017439.4:c.577-13_577-11dupTTT (chr7-77377400-C-CAAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_017439.4(GSAP):c.577-13_577-11dupTTT 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 0.00034 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00056 ( 1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSAP	NM_017439.4 link	c.577-13_577-11dupTTT		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.577-11_577-10insTTT		intron_variant	Intron 8 of 30	1	NM_017439.4	ENSP00000257626.7		A4D1B5-1
GSAP	ENST00000334003.11 link	n.468-11_468-10insTTT		intron_variant	Intron 7 of 18	2

Frequencies

GnomAD3 genomes

AF:

0.000337

AC:

AN:

98054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000602

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000484

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000949

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000215

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000564

AC:

612

AN:

1085894

Hom.:

Cov.:

AF XY:

0.000580

AC XY:

310

AN XY:

534260

show subpopulations

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

African (AFR)

AF:

0.00183

AC:

AN:

22936

American (AMR)

AF:

0.00259

AC:

AN:

20882

Ashkenazi Jewish (ASJ)

AF:

0.000335

AC:

AN:

14912

East Asian (EAS)

AF:

0.00442

AC:

106

AN:

23972

South Asian (SAS)

AF:

0.000992

AC:

AN:

52434

European-Finnish (FIN)

AF:

0.000621

AC:

AN:

24164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3056

European-Non Finnish (NFE)

AF:

0.000354

AC:

312

AN:

880894

Other (OTH)

AF:

0.000610

AC:

AN:

42644

⚠️ 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: 0.321

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000337

AC:

AN:

98058

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

AN XY:

45126

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

24938

American (AMR)

AF:

0.000484

AC:

AN:

8256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2670

East Asian (EAS)

AF:

0.000952

AC:

AN:

3150

South Asian (SAS)

AF:

0.00

AC:

AN:

2936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.000215

AC:

AN:

51060

Other (OTH)

AF:

0.00

AC:

AN:

1272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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

Splicing

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