1-201649365-C-A

Variant names:

• chr1-201649365-C-A
• NM_001389617.1:c.1558C>A

Variant summary

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

The NM_001389617.1(NAV1):​c.1558C>A​(p.Pro520Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • 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: 7.23

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]

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.1558C>A	p.Pro520Thr	missense_variant	Exon 5 of 34	ENST00000685211.1	NP_001376546.1
NAV1	NM_001389616.1	c.1558C>A	p.Pro520Thr	missense_variant	Exon 4 of 32		NP_001376545.1
NAV1	NM_001389615.1	c.1558C>A	p.Pro520Thr	missense_variant	Exon 5 of 31		NP_001376544.1
NAV1	NM_020443.5	c.697C>A	p.Pro233Thr	missense_variant	Exon 1 of 30		NP_065176.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAV1	ENST00000685211.1	c.1558C>A	p.Pro520Thr	missense_variant	Exon 5 of 34		NM_001389617.1	ENSP00000510803.1
NAV1	ENST00000367296.8	c.697C>A	p.Pro233Thr	missense_variant	Exon 1 of 30	5		ENSP00000356265.4
NAV1	ENST00000367302.5	c.736C>A	p.Pro246Thr	missense_variant	Exon 3 of 30	5		ENSP00000356271.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454892 Hom.: 0 Cov.: 55 AF XY: 0.00000138 AC XY: 1 AN XY: 723160

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.697C>A (p.P233T) alteration is located in exon 1 (coding exon 1) of the NAV1 gene. This alteration results from a C to A substitution at nucleotide position 697, causing the proline (P) at amino acid position 233 to be replaced by a threonine (T). 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	0.94
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.58	T;T
Vest4		0.59
MutPred		0.39		.;Gain of sheet (P = 0.0073);
MVP		0.20
MPC		2.2
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.51
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-201618493;