chr1-201648888-A-G

Position:

• chr1-201648888-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001389617.1(NAV1):​c.1081A>G​(p.Ser361Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAV1 NM_001389617.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.939

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048357427).
• BP6: Variant 1-201648888-A-G is Benign according to our data. Variant chr1-201648888-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2534315.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAV1	NM_001389617.1	c.1081A>G	p.Ser361Gly	missense_variant	5/34	ENST00000685211.1	NP_001376546.1
NAV1	NM_001389616.1	c.1081A>G	p.Ser361Gly	missense_variant	4/32		NP_001376545.1
NAV1	NM_001389615.1	c.1081A>G	p.Ser361Gly	missense_variant	5/31		NP_001376544.1
NAV1	NM_020443.5	c.220A>G	p.Ser74Gly	missense_variant	1/30		NP_065176.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAV1	ENST00000685211.1	c.1081A>G	p.Ser361Gly	missense_variant	5/34		NM_001389617.1	ENSP00000510803	P2
NAV1	ENST00000367296.8	c.220A>G	p.Ser74Gly	missense_variant	1/30	5		ENSP00000356265	A2
NAV1	ENST00000367302.5	c.259A>G	p.Ser87Gly	missense_variant	3/30	5		ENSP00000356271	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.60
DEOGEN2	Benign	0.020	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.62	T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.20	.;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.067
Sift	Benign	0.70	T;T
Sift4G	Benign	0.46	T;T
Vest4		0.080
MutPred		0.14		.;Loss of phosphorylation at S74 (P = 0.0167);
MVP		0.14
MPC		0.89
ClinPred		0.014	T
GERP RS		-0.30
Varity_R		0.044
gMVP		0.11

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: rs1669079488; hg19: chr1-201618016;