rs768202154

Variant names:

• chr7-77314412-C-A
• rs768202154
• NM_017439.4:c.2167G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-77314412-C-A
• chr7-77314412-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017439.4(GSAP):​c.2167G>T​(p.Val723Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V723M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GSAP NM_017439.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

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]

CCDC146 (HGNC:29296): (coiled-coil domain containing 146) Located in centriole. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.17573816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSAP	NM_017439.4	c.2167G>T	p.Val723Leu	missense_variant	Exon 27 of 31	ENST00000257626.12	NP_059135.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSAP	ENST00000257626.12	c.2167G>T	p.Val723Leu	missense_variant	Exon 27 of 31	1	NM_017439.4	ENSP00000257626.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0068	T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.085	T;T;T
Sift4G	Benign	0.27	T;D;T
Polyphen		0.98	D;.;.
Vest4		0.62
MutPred		0.34		Gain of helix (P = 0.2294);.;.;
MVP		0.30
MPC		0.37
ClinPred		0.76	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.085
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs768202154; hg19: chr7-76943729;