dbSNP rs4727380: GSAP:c.-537+25C>G (chr7-77416489-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NR_110073.1(LOC101927243):n.151+1141G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 416,368 control chromosomes in the GnomAD database, including 86,751 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.66 ( 33524 hom., cov: 34)

Exomes 𝑓: 0.63 ( 53227 hom. )

Consequence

LOC101927243
NR_110073.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0560

Publications

9 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:

ENSG00000273341 (HGNC:):

ENSG00000273341 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_110073.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LOC101927243	NR_110073.1		n.151+1141G>C	intron	N/A
GSAP	NM_017439.4	MANE Select	c.-168C>G	upstream_gene	N/A	NP_059135.2	A4D1B5-1
GSAP	NM_001350896.2		c.-168C>G	upstream_gene	N/A	NP_001337825.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ENSG00000273341	ENST00000728018.1		n.128+582G>C	intron	N/A
GSAP	ENST00000257626.12	TSL:1 MANE Select	c.-168C>G	upstream_gene	N/A	ENSP00000257626.7	A4D1B5-1
GSAP	ENST00000943097.1		c.-168C>G	upstream_gene	N/A	ENSP00000613156.1

Frequencies

GnomAD3 genomes

AF:

0.662

AC:

100532

AN:

151930

Hom.:

33474

Cov.:

show subpopulations

Gnomad AFR

AF:

0.723

Gnomad AMI

AF:

0.742

Gnomad AMR

AF:

0.672

Gnomad ASJ

AF:

0.631

Gnomad EAS

AF:

0.659

Gnomad SAS

AF:

0.446

Gnomad FIN

AF:

0.636

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.644

Gnomad OTH

AF:

0.631

GnomAD4 exome

AF:

0.632

AC:

167105

AN:

264332

Hom.:

53227

Cov.:

AF XY:

0.628

AC XY:

86505

AN XY:

137700

show subpopulations

African (AFR)

AF:

0.723

AC:

4887

AN:

6756

American (AMR)

AF:

0.663

AC:

4617

AN:

6962

Ashkenazi Jewish (ASJ)

AF:

0.632

AC:

5770

AN:

9136

East Asian (EAS)

AF:

0.626

AC:

13701

AN:

21892

South Asian (SAS)

AF:

0.479

AC:

5934

AN:

12394

European-Finnish (FIN)

AF:

0.627

AC:

14051

AN:

22408

Middle Eastern (MID)

AF:

0.619

AC:

798

AN:

1290

European-Non Finnish (NFE)

AF:

0.640

AC:

106969

AN:

167064

Other (OTH)

AF:

0.632

AC:

10378

AN:

16430

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

2929

5857

8786

11714

14643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

412

824

1236

1648

2060

<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:

0.662

AC:

100628

AN:

152036

Hom.:

33524

Cov.:

AF XY:

0.658

AC XY:

48916

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.723

AC:

30019

AN:

41518

American (AMR)

AF:

0.673

AC:

10284

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.631

AC:

2189

AN:

3468

East Asian (EAS)

AF:

0.658

AC:

3378

AN:

5132

South Asian (SAS)

AF:

0.446

AC:

2155

AN:

4830

European-Finnish (FIN)

AF:

0.636

AC:

6707

AN:

10546

Middle Eastern (MID)

AF:

0.534

AC:

156

AN:

292

European-Non Finnish (NFE)

AF:

0.644

AC:

43740

AN:

67942

Other (OTH)

AF:

0.627

AC:

1323

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1846

3692

5539

7385

9231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

798

1596

2394

3192

3990

<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:

0.650

Hom.:

4001

Bravo

AF:

0.670

Asia WGS

AF:

0.515

AC:

1782

AN:

3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.67

PhyloP100

0.056

PromoterAI

0.11

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over