1-201718508-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_001389617.1(NAV1):c.1840G>T(p.Ala614Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,457,108 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: 0.0000048 (0 hom.)
• Consequence: NAV1 NM_001389617.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.34

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 1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NAV1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAV1	NM_001389617.1	c.1840G>T	p.Ala614Ser	missense_variant	7/34	ENST00000685211.1
IPO9-AS1	NR_046696.1	n.685-30095C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAV1	ENST00000685211.1	c.1840G>T	p.Ala614Ser	missense_variant	7/34		NM_001389617.1	P2
IPO9-AS1	ENST00000413035.5	n.685-30095C>A		intron_variant, non_coding_transcript_variant		3
NAV1	ENST00000367296.8	c.979G>T	p.Ala327Ser	missense_variant	3/30	5		A2
NAV1	ENST00000367302.5	c.1018G>T	p.Ala340Ser	missense_variant	5/30	5		A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457108 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724186

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: 0.00000631

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000372 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2023

The c.979G>T (p.A327S) alteration is located in exon 3 (coding exon 3) of the NAV1 gene. This alteration results from a G to T substitution at nucleotide position 979, causing the alanine (A) at amino acid position 327 to be replaced by a serine (S). 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	0.58
BayesDel_addAF	Benign	0.0059	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.20	T;T
Vest4		0.76
MVP		0.59
MPC		1.9
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.39
gMVP		0.71

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: rs1672232174; hg19: chr1-201687636;