7-77377400-CAAAAAAAAAAAAA-CAAAAAA

Variant names:

• chr7-77377400-CAAAAAAA-C
• rs56314229
• NM_017439.4:c.577-17_577-11delTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_017439.4(GSAP):​c.577-17_577-11delTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,180,672 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.012 (2 hom.)
• Consequence: GSAP NM_017439.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.473
• 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 -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017439.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSAP	NM_017439.4	MANE Select	c.577-17_577-11delTTTTTTT		intron	N/A	NP_059135.2
	GSAP	NM_001350896.2		c.577-17_577-11delTTTTTTT		intron	N/A	NP_001337825.1
	GSAP	NM_001350897.2		c.577-17_577-11delTTTTTTT		intron	N/A	NP_001337826.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSAP	ENST00000257626.12	TSL:1 MANE Select	c.577-17_577-11delTTTTTTT		intron	N/A	ENSP00000257626.7
	GSAP	ENST00000943097.1		c.577-17_577-11delTTTTTTT		intron	N/A	ENSP00000613156.1
	GSAP	ENST00000880888.1		c.577-17_577-11delTTTTTTT		intron	N/A	ENSP00000550947.1

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 137 AN: 98070 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000643

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000605

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000316

Gnomad SAS AF: 0.000678

Gnomad FIN AF: 0.00102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0248 AC: 2367 AN: 95370 AF XY: 0.0261

Gnomad AFR exome AF: 0.00811

Gnomad AMR exome AF: 0.00884

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.00780

Gnomad FIN exome AF: 0.0581

Gnomad NFE exome AF: 0.0306

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0120 AC: 12993 AN: 1082598 Hom.: 2 AF XY: 0.0126 AC XY: 6689 AN XY: 532548

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

African (AFR) AF: 0.00314 AC: 72 AN: 22906

American (AMR) AF: 0.0102 AC: 213 AN: 20842

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 168 AN: 14852

East Asian (EAS) AF: 0.00625 AC: 150 AN: 23992

South Asian (SAS) AF: 0.0125 AC: 653 AN: 52250

European-Finnish (FIN) AF: 0.0329 AC: 791 AN: 24042

Middle Eastern (MID) AF: 0.0102 AC: 31 AN: 3052

European-Non Finnish (NFE) AF: 0.0118 AC: 10398 AN: 878112

Other (OTH) AF: 0.0122 AC: 517 AN: 42550

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00140 AC: 137 AN: 98074 Hom.: 0 Cov.: 0 AF XY: 0.00155 AC XY: 70 AN XY: 45128

African (AFR) AF: 0.000641 AC: 16 AN: 24942

American (AMR) AF: 0.000605 AC: 5 AN: 8258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2670

East Asian (EAS) AF: 0.000317 AC: 1 AN: 3150

South Asian (SAS) AF: 0.000681 AC: 2 AN: 2936

European-Finnish (FIN) AF: 0.00102 AC: 3 AN: 2950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 166

European-Non Finnish (NFE) AF: 0.00215 AC: 110 AN: 51070

Other (OTH) AF: 0.00 AC: 0 AN: 1272

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.47
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: rs56314229; hg19: chr7-77006717;