7-77311936-C-T

Variant names:

• chr7-77311936-C-T
• rs754726153
• NM_017439.4:c.2378G>A

Variant summary

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

The NM_017439.4(GSAP):​c.2378G>A​(p.Arg793Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000215 in 1,581,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: GSAP NM_017439.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.152
• Publications: 2 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.

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.2378G>A	p.Arg793Gln	missense	Exon 30 of 31	NP_059135.2	A4D1B5-1
	GSAP	NM_001350896.2		c.2378G>A	p.Arg793Gln	missense	Exon 29 of 30	NP_001337825.1
	GSAP	NM_001350897.2		c.2324G>A	p.Arg775Gln	missense	Exon 29 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.2378G>A	p.Arg793Gln	missense	Exon 30 of 31	ENSP00000257626.7	A4D1B5-1
	GSAP	ENST00000441833.6	TSL:1	c.341G>A	p.Arg114Gln	missense	Exon 7 of 8	ENSP00000415402.2	B7ZL33
	GSAP	ENST00000491796.5	TSL:1	n.1824G>A		non_coding_transcript_exon	Exon 8 of 9

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152042 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: 0.000414

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 248526 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000217 AC: 31 AN: 1429774 Hom.: 0 Cov.: 26 AF XY: 0.0000238 AC XY: 17 AN XY: 713560

African (AFR) AF: 0.00 AC: 0 AN: 32850

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.000245 AC: 21 AN: 85566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000831 AC: 9 AN: 1082986

Other (OTH) AF: 0.0000169 AC: 1 AN: 59256

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74258

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10568

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000414 AC: 5

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	0.067
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.83
DEOGEN2	Benign	0.00066	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.15
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.019
Sift	Benign	0.62	T
Sift4G	Benign	0.64	T
Polyphen		0.024	B
Vest4		0.098
MVP		0.055
MPC		0.15
ClinPred		0.12	T
GERP RS		-1.2
Varity_R		0.022
gMVP		0.12
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: 4

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

Other links and lift over

dbSNP: rs754726153; hg19: chr7-76941253; COSMIC: COSV57533692; COSMIC: COSV57533692;