chr12-77831594-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001024383.2(NAV3):c.133A>G(p.Thr45Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,614,094 control chromosomes in the GnomAD database, including 800,407 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.98 ( 72752 hom., cov: 31)

Exomes 𝑓: 1.0 ( 727655 hom. )

Consequence

NAV3
NM_001024383.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.994

Publications

29 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.353471E-7).

BP6

Variant 12-77831594-A-G is Benign according to our data. Variant chr12-77831594-A-G is described in ClinVar as [Benign]. Clinvar id is 1233716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAV3	NM_001024383.2 link	c.133A>G	p.Thr45Ala	missense_variant	Exon 1 of 40	ENST00000397909.7	NP_001019554.1	Q8IVL0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NAV3	ENST00000397909.7 link	c.133A>G	p.Thr45Ala	missense_variant	Exon 1 of 40	1	NM_001024383.2	ENSP00000381007.2	Q8IVL0-1
NAV3	ENST00000536525.6 link	c.133A>G	p.Thr45Ala	missense_variant	Exon 1 of 39	1		ENSP00000446132.2	Q8IVL0-2
NAV3	ENST00000549464.5 link	c.133A>G	p.Thr45Ala	missense_variant	Exon 1 of 10	5		ENSP00000446628.1	F8VZV4
NAV3	ENST00000550042.2 link	c.73-108725A>G		intron_variant	Intron 2 of 8	5		ENSP00000489639.1	A0A1B0GTC4

Frequencies

GnomAD3 genomes

AF:

0.977

AC:

148620

AN:

152150

Hom.:

72703

Cov.:

show subpopulations

Gnomad AFR

AF:

0.919

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.992

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.986

GnomAD2 exomes

AF:

0.994

AC:

247855

AN:

249304

AF XY:

0.996

show subpopulations

Gnomad AFR exome

AF:

0.917

Gnomad AMR exome

AF:

0.996

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.997

GnomAD4 exome

AF:

0.998

AC:

1458444

AN:

1461826

Hom.:

727655

Cov.:

AF XY:

0.998

AC XY:

725769

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.917

AC:

30701

AN:

33478

American (AMR)

AF:

0.996

AC:

44541

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26132

AN:

26132

East Asian (EAS)

AF:

1.00

AC:

39694

AN:

39694

South Asian (SAS)

AF:

1.00

AC:

86244

AN:

86256

European-Finnish (FIN)

AF:

1.00

AC:

53412

AN:

53412

Middle Eastern (MID)

AF:

0.998

AC:

5759

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111860

AN:

1111974

Other (OTH)

AF:

0.995

AC:

60101

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

173

346

518

691

864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.977

AC:

148728

AN:

152268

Hom.:

72752

Cov.:

AF XY:

0.977

AC XY:

72739

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.919

AC:

38161

AN:

41528

American (AMR)

AF:

0.992

AC:

15177

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5168

AN:

5168

South Asian (SAS)

AF:

1.00

AC:

4823

AN:

4824

European-Finnish (FIN)

AF:

1.00

AC:

10622

AN:

10622

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68019

AN:

68044

Other (OTH)

AF:

0.986

AC:

2081

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

161

322

482

643

804

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.992

Hom.:

137445

Bravo

AF:

0.974

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3853

ESP6500AA

AF:

0.916

AC:

3457

ESP6500EA

AF:

1.00

AC:

8250

ExAC

AF:

0.993

AC:

119934

Asia WGS

AF:

0.996

AC:

3464

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 08, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.011

T;.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.19

T;T;T

MetaRNN

Benign

5.4e-7

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.34

.;N;N

PhyloP100

0.99

PrimateAI

Benign

0.26

PROVEAN

Benign

0.39

N;N;N

REVEL

Benign

0.093

Sift

Benign

0.65

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.026, 0.010

MPC

0.13

ClinPred

0.0014

GERP RS

4.5

PromoterAI

-0.0056

Neutral

(source)

Varity_R

0.040

gMVP

0.14

Mutation Taster

=99/1

polymorphism (auto)

(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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chr12-77831594-A-G

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