rs4727380

Variant names:

• chr7-77416489-G-C
• rs4727380
• ENST00000728018.1:n.128+582G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000728018.1(ENSG00000273341):​n.128+582G>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: ENSG00000273341 ENST00000728018.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0560
• Publications: 9 publications found

Genes affected

ENSG00000273341 (HGNC:):

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]

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSAP	NM_017439.4	c.-168C>G		upstream_gene_variant		ENST00000257626.12	NP_059135.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000273341	ENST00000728018.1	n.128+582G>C		intron_variant	Intron 1 of 4
GSAP	ENST00000257626.12	c.-168C>G		upstream_gene_variant		1	NM_017439.4	ENSP00000257626.7
ENSG00000273341	ENST00000608884.3	n.-100G>C		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100532 AN: 151930 Hom.: 33474 Cov.: 34

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.: 3 AF XY: 0.628 AC XY: 86505 AN XY: 137700

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

GnomAD4 genome AF: 0.662 AC: 100628 AN: 152036 Hom.: 33524 Cov.: 34 AF XY: 0.658 AC XY: 48916 AN XY: 74320

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

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.67
PhyloP100		0.056
PromoterAI		0.11	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs4727380; hg19: chr7-77045806;