chr7-77377400-CAAAAA-C

Variant names:

• chr7-77377400-CAAAAA-C
• rs56314229
• NM_017439.4:c.577-15_577-11delTTTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_017439.4(GSAP):​c.577-15_577-11delTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,169,796 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.019 (5 hom.)
• Consequence: GSAP NM_017439.4 intron
• Clinical Significance: Not reported in ClinVar
• 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

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0194 (20805/1071720) while in subpopulation AMR AF= 0.0506 (1034/20438). AF 95% confidence interval is 0.048. There are 5 homozygotes in gnomad4_exome. There are 10987 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSAP	NM_017439.4	c.577-15_577-11delTTTTT		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.577-15_577-11delTTTTT		intron_variant	Intron 8 of 30	1	NM_017439.4	ENSP00000257626.7
GSAP	ENST00000334003.11	n.468-15_468-11delTTTTT		intron_variant	Intron 7 of 18	2

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 128 AN: 98072 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000727

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000316

Gnomad SAS AF: 0.00102

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000861

Gnomad OTH AF: 0.000786

GnomAD3 exomes AF: 0.0670 AC: 6387 AN: 95370 Hom.: 3 AF XY: 0.0685 AC XY: 3636 AN XY: 53048

Gnomad AFR exome AF: 0.0926

Gnomad AMR exome AF: 0.0642

Gnomad ASJ exome AF: 0.0729

Gnomad EAS exome AF: 0.0482

Gnomad SAS exome AF: 0.0848

Gnomad FIN exome AF: 0.0630

Gnomad NFE exome AF: 0.0634

Gnomad OTH exome AF: 0.0488

GnomAD4 exome AF: 0.0194 AC: 20805 AN: 1071720 Hom.: 5 AF XY: 0.0209 AC XY: 10987 AN XY: 526952

Gnomad4 AFR exome AF: 0.0384

Gnomad4 AMR exome AF: 0.0506

Gnomad4 ASJ exome AF: 0.0286

Gnomad4 EAS exome AF: 0.0216

Gnomad4 SAS exome AF: 0.0451

Gnomad4 FIN exome AF: 0.0274

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0222

GnomAD4 genome AF: 0.00133 AC: 130 AN: 98076 Hom.: 0 Cov.: 0 AF XY: 0.00148 AC XY: 67 AN XY: 45128

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.000727

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000317

Gnomad4 SAS AF: 0.00102

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000862

Gnomad4 OTH AF: 0.000786

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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;