1-201718518-C-T

Variant names:

• chr1-201718518-C-T
• rs1483137934
• NM_001389617.1:c.1850C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001389617.1(NAV1):​c.1850C>T​(p.Ala617Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,542 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NAV1 NM_001389617.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.63

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAV1	NM_001389617.1	c.1850C>T	p.Ala617Val	missense_variant	Exon 7 of 34	ENST00000685211.1	NP_001376546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAV1	ENST00000685211.1	c.1850C>T	p.Ala617Val	missense_variant	Exon 7 of 34		NM_001389617.1	ENSP00000510803.1
NAV1	ENST00000367296.8	c.989C>T	p.Ala330Val	missense_variant	Exon 3 of 30	5		ENSP00000356265.4
NAV1	ENST00000367302.5	c.1028C>T	p.Ala343Val	missense_variant	Exon 5 of 30	5		ENSP00000356271.1
IPO9-AS1	ENST00000413035.5	n.685-30105G>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458542 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725136

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.989C>T (p.A330V) alteration is located in exon 3 (coding exon 3) of the NAV1 gene. This alteration results from a C to T substitution at nucleotide position 989, causing the alanine (A) at amino acid position 330 to be replaced by a valine (V). 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	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.80
MutPred		0.11		.;Gain of MoRF binding (P = 0.126);
MVP		0.43
MPC		2.1
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.61
gMVP		0.75

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: rs1483137934; hg19: chr1-201687646;