1-162300675-A-G

Variant names:

• chr1-162300675-A-G
• NM_014697.3:c.313A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014697.3(NOS1AP):​c.313A>G​(p.Lys105Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NOS1AP NM_014697.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.03
• Publications: 0 publications found

Genes affected

NOS1AP (HGNC:16859): (nitric oxide synthase 1 adaptor protein) This gene encodes a cytosolic protein that binds to the signaling molecule, neuronal nitric oxide synthase (nNOS). This protein has a C-terminal PDZ-binding domain that mediates interactions with nNOS and an N-terminal phosphotyrosine binding (PTB) domain that binds to the small monomeric G protein, Dexras1. Studies of the related mouse and rat proteins have shown that this protein functions as an adapter protein linking nNOS to specific targets, such as Dexras1 and the synapsins. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2009]

NOS1AP Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 22

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
NOS1AP	NM_014697.3	c.313A>G	p.Lys105Glu	missense_variant	Exon 4 of 10	ENST00000361897.10	NP_055512.1
NOS1AP	NM_001164757.2	c.298A>G	p.Lys100Glu	missense_variant	Exon 4 of 10		NP_001158229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1AP	ENST00000361897.10	c.313A>G	p.Lys105Glu	missense_variant	Exon 4 of 10	1	NM_014697.3	ENSP00000355133.5
NOS1AP	ENST00000530878.5	c.298A>G	p.Lys100Glu	missense_variant	Exon 4 of 10	1		ENSP00000431586.1
NOS1AP	ENST00000430120.3	n.298A>G		non_coding_transcript_exon_variant	Exon 4 of 11	1		ENSP00000396713.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313A>G (p.K105E) alteration is located in exon 4 (coding exon 4) of the NOS1AP gene. This alteration results from a A to G substitution at nucleotide position 313, causing the lysine (K) at amino acid position 105 to be replaced by a glutamic acid (E). 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	0.67
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.50	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L
PhyloP100		6.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.18
Sift	Benign	0.14	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.77	.;P
Vest4		0.72
MutPred		0.55		.;Loss of ubiquitination at K105 (P = 0.0092);
MVP		0.34
MPC		2.0
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.94
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

hg19: chr1-162270465;