1-162069905-C-T

Variant names:

• chr1-162069905-C-T
• rs528769988
• NM_014697.3:c.-273C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014697.3(NOS1AP):​c.-273C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 184,708 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.016 (78 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (1 hom.)
• Consequence: NOS1AP NM_014697.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0130
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1AP	NM_014697.3	c.-273C>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000361897.10	NP_055512.1
NOS1AP	NM_001164757.2	c.-273C>T		5_prime_UTR_variant	Exon 1 of 10		NP_001158229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1AP	ENST00000361897.10	c.-273C>T		5_prime_UTR_variant	Exon 1 of 10	1	NM_014697.3	ENSP00000355133.5
NOS1AP	ENST00000530878.5	c.-273C>T		5_prime_UTR_variant	Exon 1 of 10	1		ENSP00000431586.1
NOS1AP	ENST00000430120.3	n.-273C>T		upstream_gene_variant		1		ENSP00000396713.3

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2460 AN: 151628 Hom.: 77 Cov.: 33

Gnomad AFR AF: 0.0572

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00322

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: 0.000309

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.00212 AC: 70 AN: 32972 Hom.: 1 Cov.: 0 AF XY: 0.00158 AC XY: 28 AN XY: 17768

African (AFR) AF: 0.0554 AC: 50 AN: 902

American (AMR) AF: 0.00130 AC: 1 AN: 772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1004

East Asian (EAS) AF: 0.00 AC: 0 AN: 1896

South Asian (SAS) AF: 0.00 AC: 0 AN: 1004

European-Finnish (FIN) AF: 0.000327 AC: 1 AN: 3060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.000452 AC: 10 AN: 22124

Other (OTH) AF: 0.00400 AC: 8 AN: 1998

GnomAD4 genome AF: 0.0162 AC: 2463 AN: 151736 Hom.: 78 Cov.: 33 AF XY: 0.0156 AC XY: 1155 AN XY: 74186

African (AFR) AF: 0.0571 AC: 2368 AN: 41478

American (AMR) AF: 0.00321 AC: 49 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67854

Other (OTH) AF: 0.0119 AC: 25 AN: 2104

Alfa AF: 0.0101 Hom.: 5

Bravo AF: 0.0181

Asia WGS AF: 0.00236 AC: 8 AN: 3410

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Uncertain	0.98
PhyloP100		-0.013
PromoterAI		0.037	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

dbSNP: rs528769988; hg19: chr1-162039695;