chr7-77377400-CAAA-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

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
• Publications: 0 publications found

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: Likely_benign. The variant received -6 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 VariationId is 402912.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 595 AR gene

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.260 AC: 5815 AN: 22398

American (AMR) AF: 0.183 AC: 3740 AN: 20414

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 3133 AN: 14552

East Asian (EAS) AF: 0.170 AC: 3986 AN: 23466

South Asian (SAS) AF: 0.218 AC: 11230 AN: 51464

European-Finnish (FIN) AF: 0.160 AC: 3749 AN: 23396

Middle Eastern (MID) AF: 0.247 AC: 732 AN: 2960

European-Non Finnish (NFE) AF: 0.217 AC: 185270 AN: 852816

Other (OTH) AF: 0.221 AC: 9160 AN: 41512

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.273 AC: 6824 AN: 25012

American (AMR) AF: 0.193 AC: 1601 AN: 8274

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 521 AN: 2672

East Asian (EAS) AF: 0.0906 AC: 285 AN: 3146

South Asian (SAS) AF: 0.284 AC: 832 AN: 2926

European-Finnish (FIN) AF: 0.110 AC: 325 AN: 2954

Middle Eastern (MID) AF: 0.229 AC: 38 AN: 166

European-Non Finnish (NFE) AF: 0.157 AC: 8039 AN: 51170

Other (OTH) AF: 0.196 AC: 250 AN: 1274

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
PhyloP100		0.0
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

Other links and lift over

dbSNP: rs56314229; hg19: chr7-77006717;