dbSNP rs771641910: NAV3:p.Arg202Gln (chr12-77968636-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001024383.2(NAV3):c.605G>A(p.Arg202Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

NAV3
NM_001024383.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.79

Publications

1 publications found

Variant links:

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

NAV3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.048072606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAV3	NM_001024383.2 link	c.605G>A	p.Arg202Gln	missense_variant	Exon 5 of 40	ENST00000397909.7	NP_001019554.1	Q8IVL0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAV3	ENST00000397909.7 link	c.605G>A	p.Arg202Gln	missense_variant	Exon 5 of 40	1	NM_001024383.2	ENSP00000381007.2		Q8IVL0-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000241

AC:

AN:

249302

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111970

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 27, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.605G>A (p.R202Q) alteration is located in exon 5 (coding exon 5) of the NAV3 gene. This alteration results from a G to A substitution at nucleotide position 605, causing the arginine (R) at amino acid position 202 to be replaced by a glutamine (Q). 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

Benign

0.061

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.0021

T;T;.;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.23

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Benign

0.0056

MetaRNN

Benign

0.048

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.0

.;.;N;N

PhyloP100

4.8

PrimateAI

Benign

0.35

PROVEAN

Benign

0.32

.;N;N;N

REVEL

Benign

0.078

Sift

Benign

0.64

.;T;T;T

Sift4G

Benign

0.85

.;T;T;T

Polyphen

0.0010, 0.0080

.;.;B;B

Vest4

0.16, 0.18

MVP

0.12

MPC

0.16

ClinPred

0.071

GERP RS

3.5

Varity_R

0.048

gMVP

0.15

Mutation Taster

=96/4

polymorphism

(source)

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

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rs771641910

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over