chr12-77831594-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: 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 VariationId 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.

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>G	p.Thr45Ala	missense	Exon 1 of 40	NP_001019554.1	Q8IVL0-1
	NAV3	NM_014903.6		c.133A>G	p.Thr45Ala	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>G	p.Thr45Ala	missense	Exon 1 of 40	ENSP00000381007.2	Q8IVL0-1
	NAV3	ENST00000536525.6	TSL:1	c.133A>G	p.Thr45Ala	missense	Exon 1 of 39	ENSP00000446132.2	Q8IVL0-2
	NAV3	ENST00000549464.5	TSL:5	c.133A>G	p.Thr45Ala	missense	Exon 1 of 10	ENSP00000446628.1	F8VZV4

Frequencies

GnomAD3 genomes AF: 0.977 AC: 148620 AN: 152150 Hom.: 72703 Cov.: 31

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

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.: 51 AF XY: 0.998 AC XY: 725769 AN XY: 727218

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

GnomAD4 genome AF: 0.977 AC: 148728 AN: 152268 Hom.: 72752 Cov.: 31 AF XY: 0.977 AC XY: 72739 AN XY: 74448

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

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.75
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.19	T
MetaRNN	Benign	5.4e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.99
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.093
Sift	Benign	0.65	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.13
ClinPred		0.0014	T
GERP RS		4.5
PromoterAI		-0.0056	Neutral
Varity_R		0.040
gMVP		0.14
Mutation Taster		=99/1	polymorphism (auto)

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; COSMIC: COSV107196301;