12-77831594-A-G

Position:

• chr12-77831594-A-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
NAV3	NM_001024383.2	c.133A>G	p.Thr45Ala	missense_variant	1/40	ENST00000397909.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAV3	ENST00000397909.7	c.133A>G	p.Thr45Ala	missense_variant	1/40	1	NM_001024383.2
NAV3	ENST00000536525.6	c.133A>G	p.Thr45Ala	missense_variant	1/39	1		P1
NAV3	ENST00000549464.5	c.133A>G	p.Thr45Ala	missense_variant	1/10	5
NAV3	ENST00000550042.2	c.73-108725A>G		intron_variant		5

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

GnomAD3 exomes AF: 0.994 AC: 247855 AN: 249304 Hom.: 123260 AF XY: 0.996 AC XY: 134648 AN XY: 135230

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 SAS 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

Gnomad4 AFR exome AF: 0.917

Gnomad4 AMR exome AF: 0.996

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.995

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

Gnomad4 AFR AF: 0.919

Gnomad4 AMR AF: 0.992

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.986

Alfa AF: 0.996 Hom.: 110816

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2021	- -

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.19	T;T;T
MetaRNN	Benign	5.4e-7	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.34	.;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.26	T
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	T
GERP RS		4.5
Varity_R		0.040
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs10735309; hg19: chr12-78225374;