1-162367380-G-C

Variant names:

• chr1-162367380-G-C
• rs115433966
• NM_014697.3:c.1434G>C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_014697.3(NOS1AP):​c.1434G>C​(p.Ser478Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000628 in 1,608,352 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: NOS1AP NM_014697.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.552

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]

ENSG00000254706 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-162367380-G-C is Benign according to our data. Variant chr1-162367380-G-C is described in ClinVar as [Benign]. Clinvar id is 496431.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.552 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1AP	NM_014697.3	c.1434G>C	p.Ser478Ser	synonymous_variant	Exon 10 of 10	ENST00000361897.10	NP_055512.1
NOS1AP	NM_001164757.2	c.1419G>C	p.Ser473Ser	synonymous_variant	Exon 10 of 10		NP_001158229.1
NOS1AP	NM_001126060.2	c.549G>C	p.Ser183Ser	synonymous_variant	Exon 2 of 2		NP_001119532.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1AP	ENST00000361897.10	c.1434G>C	p.Ser478Ser	synonymous_variant	Exon 10 of 10	1	NM_014697.3	ENSP00000355133.5
ENSG00000254706	ENST00000420220.1	c.-12+176G>C		intron_variant	Intron 2 of 3	5		ENSP00000398035.1

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 540 AN: 152236 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000774 AC: 184 AN: 237750 Hom.: 0 AF XY: 0.000579 AC XY: 75 AN XY: 129540

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.000237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000337

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.000323 AC: 470 AN: 1455998 Hom.: 2 Cov.: 31 AF XY: 0.000300 AC XY: 217 AN XY: 723806

Gnomad4 AFR exome AF: 0.0120

Gnomad4 AMR exome AF: 0.000339

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000701

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.000682

GnomAD4 genome AF: 0.00354 AC: 540 AN: 152354 Hom.: 1 Cov.: 32 AF XY: 0.00342 AC XY: 255 AN XY: 74504

Gnomad4 AFR AF: 0.0126

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.00388

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NOS1AP c.1434G>C (p.Ser478Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 100/76736 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.014939 (96/6426). This frequency is about 1494 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. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.5
DANN	Benign	0.78

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: rs115433966; hg19: chr1-162337170;