12-77940365-A-T

Variant names:

• chr12-77940365-A-T
• rs372725432
• NM_001024383.2:c.290A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001024383.2(NAV3):​c.290A>T​(p.Lys97Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K97R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NAV3 NM_001024383.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24
• Publications: 0 publications found

Genes affected

NAV3 (HGNC:15998): (neuron navigator 3) This gene belongs to the neuron navigator family and is expressed predominantly in the nervous system. The encoded protein contains coiled-coil domains and a conserved AAA domain characteristic for ATPases associated with a variety of cellular activities. This gene is similar to unc-53, a Caenorhabditis elegans gene involved in axon guidance. Multiple alternatively spliced transcript variants for this gene have been described but only one has had its full-length nature determined. [provided by RefSeq, Jul 2008]

NAV3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38262925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAV3	NM_001024383.2	c.290A>T	p.Lys97Met	missense_variant	Exon 2 of 40	ENST00000397909.7	NP_001019554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAV3	ENST00000397909.7	c.290A>T	p.Lys97Met	missense_variant	Exon 2 of 40	1	NM_001024383.2	ENSP00000381007.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;D;.;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.7	.;.;M;M
PhyloP100		3.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.5	.;D;N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Uncertain	0.0030	.;D;D;D
Polyphen		0.90, 0.92	.;.;P;P
Vest4		0.54, 0.51
MutPred		0.48		.;Loss of methylation at K97 (P = 0.0407);Loss of methylation at K97 (P = 0.0407);Loss of methylation at K97 (P = 0.0407);
MVP		0.45
MPC		0.68
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.17
gMVP		0.42
Mutation Taster		=82/18	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: rs372725432; hg19: chr12-78334145;