3-115676050-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002045.4(GAP43):c.68A>G(p.Asp23Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GAP43 NM_002045.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.64

Genes affected

GAP43 (HGNC:4140): (growth associated protein 43) The protein encoded by this gene has been termed a 'growth' or 'plasticity' protein because it is expressed at high levels in neuronal growth cones during development and axonal regeneration. This protein is considered a crucial component of an effective regenerative response in the nervous system. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAP43	NM_002045.4	c.68A>G	p.Asp23Gly	missense_variant	2/3	ENST00000305124.11
GAP43	NM_001130064.2	c.176A>G	p.Asp59Gly	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAP43	ENST00000305124.11	c.68A>G	p.Asp23Gly	missense_variant	2/3	1	NM_002045.4	P1
GAP43	ENST00000393780.3	c.176A>G	p.Asp59Gly	missense_variant	3/4	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250342 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135288

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460534 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.176A>G (p.D59G) alteration is located in exon 3 (coding exon 2) of the GAP43 gene. This alteration results from a A to G substitution at nucleotide position 176, causing the aspartic acid (D) at amino acid position 59 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.67		Loss of glycosylation at K26 (P = 0.0272);.;
MVP		0.76
MPC		0.32
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.81
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs561268447; hg19: chr3-115394897;