rs34398505

chr1-162367163-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014697.3(NOS1AP):c.1217C>T(p.Ala406Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000925 in 1,613,854 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: NOS1AP NM_014697.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.716

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046961308).
• BP6: Variant 1-162367163-C-T is Benign according to our data. Variant chr1-162367163-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1AP	NM_014697.3	c.1217C>T	p.Ala406Val	missense_variant	10/10	ENST00000361897.10
NOS1AP	NM_001164757.2	c.1202C>T	p.Ala401Val	missense_variant	10/10
NOS1AP	NM_001126060.2	c.332C>T	p.Ala111Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1AP	ENST00000361897.10	c.1217C>T	p.Ala406Val	missense_variant	10/10	1	NM_014697.3

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 712 AN: 152256 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00115 AC: 288 AN: 250726 Hom.: 3 AF XY: 0.000885 AC XY: 120 AN XY: 135654

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000535 AC: 782 AN: 1461480 Hom.: 7 Cov.: 31 AF XY: 0.000488 AC XY: 355 AN XY: 727080

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00467 AC: 711 AN: 152374 Hom.: 7 Cov.: 32 AF XY: 0.00479 AC XY: 357 AN XY: 74512

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00102 Hom.: 3

Bravo AF: 0.00507

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00133 AC: 162

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 18, 2017

Variant summary: The NOS1AP c.1217C>T (p.Ala406Val) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index). This variant was found in ExAC in 162/120512 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.013835 (142/10264). This frequency is about 1383 times the estimated maximal expected allele frequency of a pathogenic NOS1AP variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. gnomAD reporrs the variant at a frequency 0.00156 (434/276598, including 5 homozygotes). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories nor was it evaluated for functional impact by in vivo/vitro studies. Taken together, based on the frequency in general population, this variant is classified as benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 13, 2022

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.78	T;T;T;T;T
MetaRNN	Benign	0.0047	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.76	N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.65	N;N;N;N;.
REVEL	Benign	0.19
Sift	Benign	0.087	T;T;T;T;.
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.025	.;B;.;.;.
Vest4		0.12
MVP		0.68
MPC		0.99
ClinPred		0.028	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.17

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: rs34398505; hg19: chr1-162336953;