Variant 1-201718611-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_001389617.1(NAV1):c.1943G>A(p.Arg648His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

NAV1
NM_001389617.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.94

Variant links:

Genes affected

NAV1 (HGNC:15989): (neuron navigator 1) 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. The exact function of this gene is not known, but it is thought to play a role in in neuronal development and regeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

NAV1 links:

IPO9-AS1 (HGNC:40892): (IPO9 antisense RNA 1)

IPO9-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2

Missense variant where missense usually causes diseases, NAV1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.744

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAV1	NM_001389617.1 linkuse as main transcript	c.1943G>A	p.Arg648His	missense_variant	7/34	ENST00000685211.1
IPO9-AS1	NR_046696.1 linkuse as main transcript	n.685-30198C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAV1	ENST00000685211.1 linkuse as main transcript	c.1943G>A	p.Arg648His	missense_variant	7/34		NM_001389617.1	P2
IPO9-AS1	ENST00000413035.5 linkuse as main transcript	n.685-30198C>T		intron_variant, non_coding_transcript_variant		3
NAV1	ENST00000367296.8 linkuse as main transcript	c.1082G>A	p.Arg361His	missense_variant	3/30	5		A2	Q8NEY1-1
NAV1	ENST00000367302.5 linkuse as main transcript	c.1121G>A	p.Arg374His	missense_variant	5/30	5		A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.1082G>A (p.R361H) alteration is located in exon 3 (coding exon 3) of the NAV1 gene. This alteration results from a G to A substitution at nucleotide position 1082, causing the arginine (R) at amino acid position 361 to be replaced by a histidine (H). 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

Uncertain

0.36

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.74

D;D

MetaSVM

Benign

-0.59

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.0

D;D

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0060

D;D

Vest4

0.69

MutPred

0.56

.;Loss of MoRF binding (P = 0.0126);

MVP

0.55

MPC

1.0

ClinPred

0.97

GERP RS

5.6

Varity_R

0.61

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over