12-77831636-A-T

Variant names:

• chr12-77831636-A-T
• rs747682850
• NM_001024383.2:c.175A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001024383.2(NAV3):​c.175A>T​(p.Lys59*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAV3 NM_001024383.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAV3	NM_001024383.2	c.175A>T	p.Lys59*	stop_gained	Exon 1 of 40	ENST00000397909.7	NP_001019554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAV3	ENST00000397909.7	c.175A>T	p.Lys59*	stop_gained	Exon 1 of 40	1	NM_001024383.2	ENSP00000381007.2
NAV3	ENST00000536525.6	c.175A>T	p.Lys59*	stop_gained	Exon 1 of 39	1		ENSP00000446132.2
NAV3	ENST00000549464.5	c.175A>T	p.Lys59*	stop_gained	Exon 1 of 10	5		ENSP00000446628.1
NAV3	ENST00000550042.2	c.73-108683A>T		intron_variant	Intron 2 of 8	5		ENSP00000489639.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.067
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		2.3
Vest4		0.78, 0.83
GERP RS		0.16
PromoterAI		-0.052	Neutral
Mutation Taster		=5/195	disease causing (fs/PTC)

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: rs747682850; hg19: chr12-78225416;