12-77831538-T-C

Variant names:

• chr12-77831538-T-C
• rs1243631591
• NM_001024383.2:c.77T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001024383.2(NAV3):​c.77T>C​(p.Ile26Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAV3 NM_001024383.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.82

Genes affected

NAV3 (HGNC:15998): (neuron navigator 3) 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. Multiple alternatively spliced transcript variants for this gene have been described but only one has had its full-length nature determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3993478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAV3	NM_001024383.2	c.77T>C	p.Ile26Thr	missense_variant	Exon 1 of 40	ENST00000397909.7	NP_001019554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAV3	ENST00000397909.7	c.77T>C	p.Ile26Thr	missense_variant	Exon 1 of 40	1	NM_001024383.2	ENSP00000381007.2
NAV3	ENST00000536525.6	c.77T>C	p.Ile26Thr	missense_variant	Exon 1 of 39	1		ENSP00000446132.2
NAV3	ENST00000549464.5	c.77T>C	p.Ile26Thr	missense_variant	Exon 1 of 10	5		ENSP00000446628.1
NAV3	ENST00000550042.2	c.73-108781T>C		intron_variant	Intron 2 of 8	5		ENSP00000489639.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.77T>C (p.I26T) alteration is located in exon 1 (coding exon 1) of the NAV3 gene. This alteration results from a T to C substitution at nucleotide position 77, causing the isoleucine (I) at amino acid position 26 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	0.88
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.5	.;L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99, 0.98	.;D;D
Vest4		0.29, 0.29
MutPred		0.35		Gain of glycosylation at I26 (P = 0.006);Gain of glycosylation at I26 (P = 0.006);Gain of glycosylation at I26 (P = 0.006);
MVP		0.33
MPC		0.18
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.27
gMVP		0.38

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: rs1243631591; hg19: chr12-78225318;