rs199566527

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_005450.6(NOG):c.275G>A(p.Gly92Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,609,394 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 4 hom. )

Consequence

NOG
NM_005450.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 1.86

Publications

10 publications found

Variant links:

Genes affected

NOG (HGNC:7866): (noggin) The secreted polypeptide, encoded by this gene, binds and inactivates members of the transforming growth factor-beta (TGF-beta) superfamily signaling proteins, such as bone morphogenetic protein-4 (BMP4). By diffusing through extracellular matrices more efficiently than members of the TGF-beta superfamily, this protein may have a principal role in creating morphogenic gradients. The protein appears to have pleiotropic effect, both early in development as well as in later stages. It was originally isolated from Xenopus based on its ability to restore normal dorsal-ventral body axis in embryos that had been artificially ventralized by UV treatment. The results of the mouse knockout of the ortholog suggest that it is involved in numerous developmental processes, such as neural tube fusion and joint formation. Recently, several dominant human NOG mutations in unrelated families with proximal symphalangism (SYM1) and multiple synostoses syndrome (SYNS1) were identified; both SYM1 and SYNS1 have multiple joint fusion as their principal feature, and map to the same region (17q22) as this gene. All of these mutations altered evolutionarily conserved amino acid residues. The amino acid sequence of this human gene is highly homologous to that of Xenopus, rat and mouse. [provided by RefSeq, Jul 2008]

NOG Gene-Disease associations (from GenCC):

multiple synostoses syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
NOG-related symphalangism spectrum disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
brachydactyly type B2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
multiple synostoses syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
proximal symphalangism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
stapes ankylosis with broad thumbs and toes
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
tarsal-carpal coalition syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NOG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a chain Noggin (size 204) in uniprot entity NOGG_HUMAN there are 27 pathogenic changes around while only 2 benign (93%) in NM_005450.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 1.318 (below the threshold of 3.09). Trascript score misZ: 1.4011 (below the threshold of 3.09). GenCC associations: The gene is linked to stapes ankylosis with broad thumbs and toes, multiple synostoses syndrome, brachydactyly type B2, proximal symphalangism, tarsal-carpal coalition syndrome, multiple synostoses syndrome 1, NOG-related symphalangism spectrum disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.021610886).

BP6

Variant 17-56594498-G-A is Benign according to our data. Variant chr17-56594498-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377073.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00172 (262/152242) while in subpopulation NFE AF = 0.00298 (203/68012). AF 95% confidence interval is 0.00265. There are 1 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 262 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOG	NM_005450.6 link	c.275G>A	p.Gly92Glu	missense_variant	Exon 1 of 1	ENST00000332822.6	NP_005441.1	Q13253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOG	ENST00000332822.6 link	c.275G>A	p.Gly92Glu	missense_variant	Exon 1 of 1	6	NM_005450.6	ENSP00000328181.4		Q13253

Frequencies

GnomAD3 genomes

AF:

0.00172

AC:

262

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00298

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00165

AC:

383

AN:

231998

AF XY:

0.00181

show subpopulations

Gnomad AFR exome

AF:

0.000916

Gnomad AMR exome

AF:

0.00201

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000143

Gnomad NFE exome

AF:

0.00274

Gnomad OTH exome

AF:

0.00175

GnomAD4 exome

AF:

0.00219

AC:

3184

AN:

1457152

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

1565

AN XY:

724528

show subpopulations

African (AFR)

AF:

0.000510

AC:

AN:

33358

American (AMR)

AF:

0.00201

AC:

AN:

44388

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25968

East Asian (EAS)

AF:

0.00

AC:

AN:

39600

South Asian (SAS)

AF:

0.000523

AC:

AN:

86020

European-Finnish (FIN)

AF:

0.000115

AC:

AN:

51992

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00263

AC:

2917

AN:

1109962

Other (OTH)

AF:

0.00180

AC:

108

AN:

60106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

192

384

577

769

961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00172

AC:

262

AN:

152242

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41554

American (AMR)

AF:

0.00170

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00298

AC:

203

AN:

68012

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00267

Hom.:

Bravo

AF:

0.00193

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000474

AC:

ESP6500EA

AF:

0.00316

AC:

ExAC

AF:

0.00171

AC:

203

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NOG: BS1, BS2 -

not specified

Uncertain:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant was identified as de novo in one individual with fibrodysplasia ossificans progressiva (Semonin 2001). 0.3% frequency too high for AD disease with high penetrance. -

NOG-related disorder

Benign:1

Oct 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

Eigen

Benign

-0.034

Eigen_PC

Benign

0.017

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.022

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.2

PhyloP100

1.9

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.36

REVEL

Uncertain

0.55

Sift

Benign

0.045

Sift4G

Uncertain

0.058

Polyphen

0.91

Vest4

0.34

MVP

0.87

MPC

2.1

ClinPred

0.014

GERP RS

3.1

Varity_R

0.079

gMVP

0.32

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over