chr7-77314412-C-T

Variant names:

• chr7-77314412-C-T
• rs768202154
• NM_017439.4:c.2167G>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.2167G>A​(p.Val723Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GSAP NM_017439.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02
• 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=0.19599429).

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.2167G>A	p.Val723Met	missense	Exon 27 of 31	NP_059135.2	A4D1B5-1
	GSAP	NM_001350896.2		c.2167G>A	p.Val723Met	missense	Exon 26 of 30	NP_001337825.1
	GSAP	NM_001350897.2		c.2113G>A	p.Val705Met	missense	Exon 26 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.2167G>A	p.Val723Met	missense	Exon 27 of 31	ENSP00000257626.7	A4D1B5-1
	GSAP	ENST00000441833.6	TSL:1	c.130G>A	p.Val44Met	missense	Exon 4 of 8	ENSP00000415402.2	B7ZL33
	GSAP	ENST00000491796.5	TSL:1	n.1613G>A		non_coding_transcript_exon	Exon 5 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249302 AF XY: 0.00000739

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: 0.0000464

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461548 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727100

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111756

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000331 AC: 4

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	0.17
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T
Eigen	Benign	0.0040
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.62
MVP		0.35
MPC		0.53
ClinPred		0.78	D
GERP RS		3.8
Varity_R		0.13
gMVP		0.59
Mutation Taster		=85/15	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: rs768202154; hg19: chr7-76943729;