Genetic Variant NM_017439.4:c.577-12_577-11dupTT (chr7-77377400-C-CAA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_017439.4(GSAP):c.577-12_577-11dupTT 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 0.013 ( 27 hom., cov: 0)

Exomes 𝑓: 0.0044 ( 2 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

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.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0132 (1295/98022) while in subpopulation AMR AF = 0.0383 (316/8246). AF 95% confidence interval is 0.0348. There are 27 homozygotes in GnomAd4. There are 629 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 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.577-12_577-11dupTT	intron	N/A	NP_059135.2	A4D1B5-1
GSAP	NM_001350896.2		c.577-12_577-11dupTT	intron	N/A	NP_001337825.1
GSAP	NM_001350897.2		c.577-12_577-11dupTT	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.577-11_577-10insTT	intron	N/A	ENSP00000257626.7	A4D1B5-1
GSAP	ENST00000943097.1		c.577-11_577-10insTT	intron	N/A	ENSP00000613156.1
GSAP	ENST00000880888.1		c.577-11_577-10insTT	intron	N/A	ENSP00000550947.1

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

1297

AN:

98020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0238

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0386

Gnomad ASJ

AF:

0.00412

Gnomad EAS

AF:

0.0245

Gnomad SAS

AF:

0.00780

Gnomad FIN

AF:

0.000339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00509

Gnomad OTH

AF:

0.0118

GnomAD4 exome

AF:

0.00437

AC:

4731

AN:

1082486

Hom.:

Cov.:

AF XY:

0.00429

AC XY:

2284

AN XY:

532692

show subpopulations

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

African (AFR)

AF:

0.0139

AC:

317

AN:

22752

American (AMR)

AF:

0.0137

AC:

285

AN:

20784

Ashkenazi Jewish (ASJ)

AF:

0.00329

AC:

AN:

14890

East Asian (EAS)

AF:

0.0236

AC:

560

AN:

23770

South Asian (SAS)

AF:

0.00560

AC:

293

AN:

52328

European-Finnish (FIN)

AF:

0.00352

AC:

AN:

24120

Middle Eastern (MID)

AF:

0.00527

AC:

AN:

3038

European-Non Finnish (NFE)

AF:

0.00331

AC:

2903

AN:

878330

Other (OTH)

AF:

0.00525

AC:

223

AN:

42474

⚠️ 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: 0.316

Heterozygous variant carriers

334

668

1001

1335

1669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

142

284

426

568

710

<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:

0.0132

AC:

1295

AN:

98022

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

629

AN XY:

45102

show subpopulations

African (AFR)

AF:

0.0238

AC:

593

AN:

24928

American (AMR)

AF:

0.0383

AC:

316

AN:

8246

Ashkenazi Jewish (ASJ)

AF:

0.00412

AC:

AN:

2670

East Asian (EAS)

AF:

0.0246

AC:

AN:

3134

South Asian (SAS)

AF:

0.00750

AC:

AN:

2934

European-Finnish (FIN)

AF:

0.000339

AC:

AN:

2950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.00509

AC:

260

AN:

51062

Other (OTH)

AF:

0.0118

AC:

AN:

1272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

137

182

228

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 v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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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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