chr1-162070223-C-G

Position:

• chr1-162070223-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014697.3(NOS1AP):​c.46C>G​(p.Leu16Val) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOS1AP NM_014697.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14567995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1AP	NM_014697.3	c.46C>G	p.Leu16Val	missense_variant	1/10	ENST00000361897.10
NOS1AP	NM_001164757.2	c.46C>G	p.Leu16Val	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1AP	ENST00000361897.10	c.46C>G	p.Leu16Val	missense_variant	1/10	1	NM_014697.3
NOS1AP	ENST00000530878.5	c.46C>G	p.Leu16Val	missense_variant	1/10	1		P1
NOS1AP	ENST00000430120.3	c.46C>G	p.Leu16Val	missense_variant, NMD_transcript_variant	1/11	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

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

Mar 14, 2023

The c.46C>G (p.L16V) alteration is located in exon 1 (coding exon 1) of the NOS1AP gene. This alteration results from a C to G substitution at nucleotide position 46, causing the leucine (L) at amino acid position 16 to be replaced by a valine (V). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;T
Eigen	Benign	-0.096
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.036
Sift	Benign	0.18	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.96	.;D
Vest4		0.26
MutPred		0.43		Loss of catalytic residue at L16 (P = 0.0172);Loss of catalytic residue at L16 (P = 0.0172);
MVP		0.42
MPC		1.4
ClinPred		0.40	T
GERP RS		1.3
Varity_R		0.068
gMVP		0.80

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: rs1691631574; hg19: chr1-162040013;