NM_001024383.2:c.133A>T

Variant names:

• chr12-77831594-A-T
• rs10735309
• NM_001024383.2:c.133A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001024383.2(NAV3):​c.133A>T​(p.Thr45Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. T45A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NAV3 NM_001024383.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.994
• Publications: 29 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03572923).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024383.2. 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
	NAV3	NM_001024383.2	MANE Select	c.133A>T	p.Thr45Ser	missense	Exon 1 of 40	NP_001019554.1	Q8IVL0-1
	NAV3	NM_014903.6		c.133A>T	p.Thr45Ser	missense	Exon 1 of 39	NP_055718.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAV3	ENST00000397909.7	TSL:1 MANE Select	c.133A>T	p.Thr45Ser	missense	Exon 1 of 40	ENSP00000381007.2	Q8IVL0-1
	NAV3	ENST00000536525.6	TSL:1	c.133A>T	p.Thr45Ser	missense	Exon 1 of 39	ENSP00000446132.2	Q8IVL0-2
	NAV3	ENST00000549464.5	TSL:5	c.133A>T	p.Thr45Ser	missense	Exon 1 of 10	ENSP00000446628.1	F8VZV4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249304 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: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000958 AC: 14 AN: 1461832 Hom.: 0 Cov.: 51 AF XY: 0.00000688 AC XY: 5 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68052

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00000358 Hom.: 137445

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.99
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.065
Sift	Benign	0.16	T
Sift4G	Benign	0.71	T
Polyphen		0.0040	B
Vest4		0.057
MutPred		0.12		Gain of phosphorylation at T45 (P = 0.0357)
MVP		0.18
MPC		0.13
ClinPred		0.051	T
GERP RS		4.5
PromoterAI		-0.028	Neutral
Varity_R		0.055
gMVP		0.14
Mutation Taster		=85/15	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: rs10735309; hg19: chr12-78225374;