17-56594498-G-A

Position:

chr17-56594498-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a chain Noggin (size 204) in uniprot entity NOGG_HUMAN there are 28 pathogenic changes around while only 4 benign (88%) in NM_005450.6

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 id is 377073.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr17-56594498-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 262 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOG	NM_005450.6 linkuse as main transcript	c.275G>A	p.Gly92Glu	missense_variant	1/1	ENST00000332822.6	NP_005441.1	Q13253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOG	ENST00000332822.6 linkuse as main transcript	c.275G>A	p.Gly92Glu	missense_variant	1/1	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

GnomAD3 exomes

AF:

0.00165

AC:

383

AN:

231998

Hom.:

AF XY:

0.00181

AC XY:

232

AN XY:

128184

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 SAS exome

AF:

0.000398

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

Gnomad4 AFR exome

AF:

0.000510

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000523

Gnomad4 FIN exome

AF:

0.000115

Gnomad4 NFE exome

AF:

0.00263

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.00172

AC:

262

AN:

152242

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00298

Gnomad4 OTH

AF:

0.00237

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

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	NOG: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2019

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

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

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over