rs118149283

Variant names:

• chr12-77966309-A-G
• rs118149283
• NM_001024383.2:c.487+8A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001024383.2(NAV3):​c.487+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00971 in 1,605,342 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0099 (102 hom.)
• Consequence: NAV3 NM_001024383.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001151
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.929
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-77966309-A-G is Benign according to our data. Variant chr12-77966309-A-G is described in ClinVar as [Benign]. Clinvar id is 774821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAV3	NM_001024383.2	c.487+8A>G		splice_region_variant, intron_variant	Intron 4 of 39	ENST00000397909.7	NP_001019554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAV3	ENST00000397909.7	c.487+8A>G		splice_region_variant, intron_variant	Intron 4 of 39	1	NM_001024383.2	ENSP00000381007.2

Frequencies

GnomAD3 genomes AF: 0.00809 AC: 1231 AN: 152164 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00987

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00924 AC: 2256 AN: 244214 AF XY: 0.00960

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0263

Gnomad NFE exome AF: 0.00876

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00988 AC: 14358 AN: 1453060 Hom.: 102 Cov.: 28 AF XY: 0.0103 AC XY: 7439 AN XY: 722804

African (AFR) AF: 0.00118 AC: 39 AN: 33140

American (AMR) AF: 0.00250 AC: 109 AN: 43666

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 278 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.0148 AC: 1255 AN: 84558

European-Finnish (FIN) AF: 0.0265 AC: 1413 AN: 53382

Middle Eastern (MID) AF: 0.0159 AC: 91 AN: 5736

European-Non Finnish (NFE) AF: 0.00962 AC: 10644 AN: 1106966

Other (OTH) AF: 0.00881 AC: 529 AN: 60074

GnomAD4 genome AF: 0.00809 AC: 1232 AN: 152282 Hom.: 13 Cov.: 33 AF XY: 0.00907 AC XY: 675 AN XY: 74456

African (AFR) AF: 0.00185 AC: 77 AN: 41576

American (AMR) AF: 0.00458 AC: 70 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00923 AC: 32 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0149 AC: 72 AN: 4822

European-Finnish (FIN) AF: 0.0277 AC: 294 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00987 AC: 671 AN: 68010

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00966 Hom.: 4

Bravo AF: 0.00580

Asia WGS AF: 0.00462 AC: 16 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.0
DANN	Benign	0.77
PhyloP100		0.93
PromoterAI		-0.0048	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs118149283; hg19: chr12-78360089;