NM_017439.4:c.1313A>G

Variant names:

• chr7-77355238-T-C
• rs146379296
• NM_017439.4:c.1313A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_017439.4(GSAP):​c.1313A>G​(p.Gln438Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000586 in 1,613,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (0 hom.)
• Consequence: GSAP NM_017439.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.836
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016632646).
• BP6: Variant 7-77355238-T-C is Benign according to our data. Variant chr7-77355238-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2454741.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1313A>G	p.Gln438Arg	missense	Exon 16 of 31	NP_059135.2	A4D1B5-1
	GSAP	NM_001350896.2		c.1313A>G	p.Gln438Arg	missense	Exon 16 of 30	NP_001337825.1
	GSAP	NM_001350897.2		c.1313A>G	p.Gln438Arg	missense	Exon 16 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.1313A>G	p.Gln438Arg	missense	Exon 16 of 31	ENSP00000257626.7	A4D1B5-1
	GSAP	ENST00000943097.1		c.1313A>G	p.Gln438Arg	missense	Exon 16 of 30	ENSP00000613156.1
	GSAP	ENST00000880888.1		c.1313A>G	p.Gln438Arg	missense	Exon 16 of 30	ENSP00000550947.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000296 AC: 74 AN: 249586 AF XY: 0.000319

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000605

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000595 AC: 870 AN: 1461018 Hom.: 0 Cov.: 30 AF XY: 0.000576 AC XY: 419 AN XY: 726858

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000737 AC: 819 AN: 1111294

Other (OTH) AF: 0.000530 AC: 32 AN: 60364

GnomAD4 genome AF: 0.000492 AC: 75 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74494

African (AFR) AF: 0.0000481 AC: 2 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68014

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000561 Hom.: 0

Bravo AF: 0.000325

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000873

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.056
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0050
DANN	Benign	0.11
DEOGEN2	Benign	0.00074	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.41	N
PhyloP100		-0.84
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.0070
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MVP		0.030
MPC		0.14
ClinPred		0.011	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.13
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs146379296; hg19: chr7-76984555;