7-77377400-CAAAAAAAAAAAAA-CAAAAAAAAAAAAAA

Variant names:

• chr7-77377400-C-CA
• rs56314229
• NM_017439.4:c.577-11dupT

Variant summary

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

The NM_017439.4(GSAP):​c.577-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.098 (641 hom., cov: 0)
  • Exomes 𝑓: 0.026 (12 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSAP NM_017439.4 intron
• Clinical Significance: Not reported in ClinVar
• 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 -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 12 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.577-11dupT		intron	N/A	NP_059135.2	A4D1B5-1
	GSAP	NM_001350896.2		c.577-11dupT		intron	N/A	NP_001337825.1
	GSAP	NM_001350897.2		c.577-11dupT		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.577-11_577-10insT		intron	N/A	ENSP00000257626.7	A4D1B5-1
	GSAP	ENST00000943097.1		c.577-11_577-10insT		intron	N/A	ENSP00000613156.1
	GSAP	ENST00000880888.1		c.577-11_577-10insT		intron	N/A	ENSP00000550947.1

Frequencies

GnomAD3 genomes AF: 0.0978 AC: 9566 AN: 97774 Hom.: 642 Cov.: 0

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00606

Gnomad AMR AF: 0.0975

Gnomad ASJ AF: 0.0678

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.0762

Gnomad FIN AF: 0.0671

Gnomad MID AF: 0.0977

Gnomad NFE AF: 0.0587

Gnomad OTH AF: 0.0990

GnomAD4 exome AF: 0.0262 AC: 28121 AN: 1072836 Hom.: 12 Cov.: 0 AF XY: 0.0255 AC XY: 13477 AN XY: 528232

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

African (AFR) AF: 0.0593 AC: 1324 AN: 22326

American (AMR) AF: 0.0279 AC: 577 AN: 20704

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 261 AN: 14810

East Asian (EAS) AF: 0.0961 AC: 2251 AN: 23412

South Asian (SAS) AF: 0.0196 AC: 1024 AN: 52114

European-Finnish (FIN) AF: 0.0199 AC: 477 AN: 23992

Middle Eastern (MID) AF: 0.0286 AC: 86 AN: 3010

European-Non Finnish (NFE) AF: 0.0239 AC: 20820 AN: 870430

Other (OTH) AF: 0.0309 AC: 1301 AN: 42038

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0978 AC: 9565 AN: 97778 Hom.: 641 Cov.: 0 AF XY: 0.0961 AC XY: 4324 AN XY: 45002

African (AFR) AF: 0.158 AC: 3931 AN: 24826

American (AMR) AF: 0.0979 AC: 804 AN: 8214

Ashkenazi Jewish (ASJ) AF: 0.0678 AC: 181 AN: 2670

East Asian (EAS) AF: 0.350 AC: 1090 AN: 3116

South Asian (SAS) AF: 0.0768 AC: 225 AN: 2928

European-Finnish (FIN) AF: 0.0671 AC: 196 AN: 2920

Middle Eastern (MID) AF: 0.104 AC: 17 AN: 164

European-Non Finnish (NFE) AF: 0.0587 AC: 2993 AN: 51018

Other (OTH) AF: 0.0983 AC: 124 AN: 1262

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56314229;

hg19: chr7-77006717;

COSMIC: COSV57534624;