1-201649324-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001389617.1(NAV1):c.1517C>A(p.Ser506Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NAV1 NM_001389617.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NAV1
• BP4: Computational evidence support a benign effect (MetaRNN=0.13733056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAV1	NM_001389617.1	c.1517C>A	p.Ser506Tyr	missense_variant	5/34	ENST00000685211.1
NAV1	NM_001389616.1	c.1517C>A	p.Ser506Tyr	missense_variant	4/32
NAV1	NM_001389615.1	c.1517C>A	p.Ser506Tyr	missense_variant	5/31
NAV1	NM_020443.5	c.656C>A	p.Ser219Tyr	missense_variant	1/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAV1	ENST00000685211.1	c.1517C>A	p.Ser506Tyr	missense_variant	5/34		NM_001389617.1	P2
NAV1	ENST00000367296.8	c.656C>A	p.Ser219Tyr	missense_variant	1/30	5		A2
NAV1	ENST00000367302.5	c.695C>A	p.Ser232Tyr	missense_variant	3/30	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460038 Hom.: 0 Cov.: 55 AF XY: 0.00000138 AC XY: 1 AN XY: 726294

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: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Oct 26, 2022

The c.656C>A (p.S219Y) 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 656, causing the serine (S) at amino acid position 219 to be replaced by a tyrosine (Y). 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	Benign	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.98	N;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.064
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.028	D;D
Vest4		0.21
MutPred		0.18		.;Loss of relative solvent accessibility (P = 0.0186);
MVP		0.13
MPC		1.3
ClinPred		0.23	T
GERP RS		4.7
Varity_R		0.17
gMVP		0.21

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: chr1-201618452;