rs199566527

chr17-56594498-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.86

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM1: In a chain Noggin (size 204) in uniprot entity NOGG_HUMAN there are 53 pathogenic changes around while only 6 benign (90%) 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=3, 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 GnomAd at 262 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOG	NM_005450.6	c.275G>A	p.Gly92Glu	missense_variant	1/1	ENST00000332822.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOG	ENST00000332822.6	c.275G>A	p.Gly92Glu	missense_variant	1/1		NM_005450.6	P1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152124 Hom.: 1 Cov.: 33

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.: 0 AF XY: 0.00181 AC XY: 232 AN XY: 128184

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.: 4 Cov.: 32 AF XY: 0.00216 AC XY: 1565 AN XY: 724528

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.: 1 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74440

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.: 0

Bravo AF: 0.00193

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000474 AC: 2

ESP6500EA AF: 0.00316 AC: 26

ExAC AF: 0.00171 AC: 203

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

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	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	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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, criteria provided, single submitter

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	T
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.034
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.022	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.92	N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.36	N
REVEL	Uncertain	0.55
Sift	Benign	0.045	D
Sift4G	Uncertain	0.058	T
Polyphen		0.91	P
Vest4		0.34
MVP		0.87
MPC		2.1
ClinPred		0.014	T
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

Other links and lift over

dbSNP: rs199566527; hg19: chr17-54671859;