7-77377400-CAAA-C

Variant names:

• chr7-77377400-CAAA-C
• rs56314229
• NM_017439.4:c.577-13_577-11delTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_017439.4(GSAP):​c.577-13_577-11delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,052,978 control chromosomes in the GnomAD database, including 595 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (1373 hom., cov: 0)
  • Exomes 𝑓: 0.22 (595 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSAP NM_017439.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 7-77377400-CAAA-C is Benign according to our data. Variant chr7-77377400-CAAA-C is described in ClinVar as [Benign]. Clinvar id is 402912.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSAP	NM_017439.4	c.577-13_577-11delTTT		intron_variant	Intron 8 of 30	ENST00000257626.12	NP_059135.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSAP	ENST00000257626.12	c.577-13_577-11delTTT		intron_variant	Intron 8 of 30	1	NM_017439.4	ENSP00000257626.7
GSAP	ENST00000334003.11	n.468-13_468-11delTTT		intron_variant	Intron 7 of 18	2

Frequencies

GnomAD3 genomes AF: 0.191 AC: 18779 AN: 98256 Hom.: 1367 Cov.: 0

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.0903

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.227

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.194

GnomAD2 exomes AF: 0.168 AC: 16013 AN: 95370 AF XY: 0.165

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.165

Gnomad EAS exome AF: 0.149

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.215 AC: 226815 AN: 1052978 Hom.: 595 AF XY: 0.214 AC XY: 110682 AN XY: 518066

Gnomad4 AFR exome AF: 0.260 AC: 5815 AN: 22398

Gnomad4 AMR exome AF: 0.183 AC: 3740 AN: 20414

Gnomad4 ASJ exome AF: 0.215 AC: 3133 AN: 14552

Gnomad4 EAS exome AF: 0.170 AC: 3986 AN: 23466

Gnomad4 SAS exome AF: 0.218 AC: 11230 AN: 51464

Gnomad4 FIN exome AF: 0.160 AC: 3749 AN: 23396

Gnomad4 NFE exome AF: 0.217 AC: 185270 AN: 852816

Gnomad4 Remaining exome AF: 0.221 AC: 9160 AN: 41512

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.191 AC: 18794 AN: 98260 Hom.: 1373 Cov.: 0 AF XY: 0.195 AC XY: 8809 AN XY: 45238

Gnomad4 AFR AF: 0.273 AC: 0.272829 AN: 0.272829

Gnomad4 AMR AF: 0.193 AC: 0.193498 AN: 0.193498

Gnomad4 ASJ AF: 0.195 AC: 0.194985 AN: 0.194985

Gnomad4 EAS AF: 0.0906 AC: 0.0905912 AN: 0.0905912

Gnomad4 SAS AF: 0.284 AC: 0.284347 AN: 0.284347

Gnomad4 FIN AF: 0.110 AC: 0.11002 AN: 0.11002

Gnomad4 NFE AF: 0.157 AC: 0.157104 AN: 0.157104

Gnomad4 OTH AF: 0.196 AC: 0.196232 AN: 0.196232

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs56314229; hg19: chr7-77006717;