chr7-77355385-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_017439.4(GSAP):c.1166C>T(p.Ser389Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,611,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
GSAP
NM_017439.4 missense
NM_017439.4 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 1.35
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.1088385).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GSAP | NM_017439.4 | c.1166C>T | p.Ser389Leu | missense_variant | 16/31 | ENST00000257626.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GSAP | ENST00000257626.12 | c.1166C>T | p.Ser389Leu | missense_variant | 16/31 | 1 | NM_017439.4 | P1 | |
GSAP | ENST00000334003.11 | n.1057C>T | non_coding_transcript_exon_variant | 15/19 | 2 | ||||
GSAP | ENST00000449779.5 | n.122C>T | non_coding_transcript_exon_variant | 2/16 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000664 AC: 1AN: 150562Hom.: 0 Cov.: 31
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000320 AC: 8AN: 250270Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135298
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GnomAD4 exome AF: 0.00000890 AC: 13AN: 1460488Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 726674
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GnomAD4 genome ? AF: 0.00000664 AC: 1AN: 150562Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1AN XY: 73370
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 28, 2023 | The c.1166C>T (p.S389L) alteration is located in exon 16 (coding exon 16) of the GSAP gene. This alteration results from a C to T substitution at nucleotide position 1166, causing the serine (S) at amino acid position 389 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Loss of disorder (P = 0.0491);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at