NM_017439.4:c.2499C>A

Variant names:

• chr7-77311424-G-T
• rs1562874062
• NM_017439.4:c.2499C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017439.4(GSAP):​c.2499C>A​(p.Asp833Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,609,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GSAP NM_017439.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22
• 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]

CCDC146 (HGNC:29296): (coiled-coil domain containing 146) Located in centriole. [provided by Alliance of Genome Resources, Apr 2022]

CCDC146 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21523002).

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.2499C>A	p.Asp833Glu	missense	Exon 31 of 31	NP_059135.2	A4D1B5-1
	GSAP	NM_001350896.2		c.2499C>A	p.Asp833Glu	missense	Exon 30 of 30	NP_001337825.1
	GSAP	NM_001350897.2		c.2445C>A	p.Asp815Glu	missense	Exon 30 of 30	NP_001337826.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSAP	ENST00000257626.12	TSL:1 MANE Select	c.2499C>A	p.Asp833Glu	missense	Exon 31 of 31	ENSP00000257626.7	A4D1B5-1
	GSAP	ENST00000441833.6	TSL:1	c.462C>A	p.Asp154Glu	missense	Exon 8 of 8	ENSP00000415402.2	B7ZL33
	GSAP	ENST00000491796.5	TSL:1	n.1945C>A		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457578 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 725430

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1108288

Other (OTH) AF: 0.0000166 AC: 1 AN: 60228

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0030	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.033
Sift	Benign	0.20	T
Sift4G	Benign	0.27	T
Polyphen		0.86	P
Vest4		0.20
MutPred		0.32		Loss of helix (P = 0.0558)
MVP		0.29
MPC		0.39
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.079
gMVP		0.090
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs1562874062; hg19: chr7-76940741;