rs528385235

Variant names:

• chr12-77940421-A-G
• rs528385235
• NM_001024383.2:c.346A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001024383.2(NAV3):​c.346A>G​(p.Ile116Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,612,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: NAV3 NM_001024383.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19759846).

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.346A>G	p.Ile116Val	missense	Exon 2 of 40	NP_001019554.1	Q8IVL0-1
	NAV3	NM_014903.6		c.346A>G	p.Ile116Val	missense	Exon 2 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.346A>G	p.Ile116Val	missense	Exon 2 of 40	ENSP00000381007.2	Q8IVL0-1
	NAV3	ENST00000536525.6	TSL:1	c.346A>G	p.Ile116Val	missense	Exon 2 of 39	ENSP00000446132.2	Q8IVL0-2
	NAV3	ENST00000549464.5	TSL:5	c.346A>G	p.Ile116Val	missense	Exon 2 of 10	ENSP00000446628.1	F8VZV4

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000282 AC: 7 AN: 248544 AF XY: 0.0000297

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: 0.0000532

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000459 AC: 67 AN: 1460078 Hom.: 0 Cov.: 29 AF XY: 0.0000551 AC XY: 40 AN XY: 726426

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.000112 AC: 5 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1110648

Other (OTH) AF: 0.0000663 AC: 4 AN: 60320

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74476

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.000196 AC: 3 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000495 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000497 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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	Uncertain	0.46
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.090	N
PhyloP100		7.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.23
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.046	D
Polyphen		0.84	P
Vest4		0.31
MVP		0.10
MPC		0.11
ClinPred		0.46	T
GERP RS		5.6
Varity_R		0.18
gMVP		0.54
Mutation Taster		=68/32	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: rs528385235; hg19: chr12-78334201;