1-162287491-A-G

Variant names:

• chr1-162287491-A-G
• rs78377538
• NM_014697.3:c.270+55A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014697.3(NOS1AP):​c.270+55A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,149,020 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (37 hom.)
• Consequence: NOS1AP NM_014697.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-162287491-A-G is Benign according to our data. Variant chr1-162287491-A-G is described in ClinVar as [Benign]. Clinvar id is 1226935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1AP	NM_014697.3	c.270+55A>G		intron_variant	Intron 3 of 9	ENST00000361897.10	NP_055512.1
NOS1AP	NM_001164757.2	c.270+55A>G		intron_variant	Intron 3 of 9		NP_001158229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1AP	ENST00000361897.10	c.270+55A>G		intron_variant	Intron 3 of 9	1	NM_014697.3	ENSP00000355133.5
NOS1AP	ENST00000530878.5	c.270+55A>G		intron_variant	Intron 3 of 9	1		ENSP00000431586.1
NOS1AP	ENST00000430120.3	n.270+55A>G		intron_variant	Intron 3 of 10	1		ENSP00000396713.3

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2367 AN: 152176 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.00181 AC: 1803 AN: 996726 Hom.: 37 AF XY: 0.00155 AC XY: 798 AN XY: 516460

African (AFR) AF: 0.0560 AC: 1375 AN: 24574

American (AMR) AF: 0.00310 AC: 137 AN: 44174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23234

East Asian (EAS) AF: 0.00 AC: 0 AN: 37622

South Asian (SAS) AF: 0.000156 AC: 12 AN: 77048

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53182

Middle Eastern (MID) AF: 0.00335 AC: 16 AN: 4772

European-Non Finnish (NFE) AF: 0.000164 AC: 113 AN: 687048

Other (OTH) AF: 0.00328 AC: 148 AN: 45072

GnomAD4 genome AF: 0.0156 AC: 2374 AN: 152294 Hom.: 61 Cov.: 32 AF XY: 0.0152 AC XY: 1134 AN XY: 74470

African (AFR) AF: 0.0542 AC: 2251 AN: 41566

American (AMR) AF: 0.00542 AC: 83 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68022

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.0324 Hom.: 26

Bravo AF: 0.0174

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 25, 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	-0.87
CADD	Benign	0.028
DANN	Benign	0.56
PhyloP100		-1.1
Mutation Taster		=100/0	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

dbSNP: rs78377538; hg19: chr1-162257281;