17-56594326-C-T

Variant names:

• chr17-56594326-C-T
• rs28937580
• NM_005450.6:c.103C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_005450.6(NOG):​c.103C>T​(p.Pro35Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P35A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOG NM_005450.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 5.90

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 Pathogenic. Variant got 12 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
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-56594326-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-56594326-C-T is Pathogenic according to our data. Variant chr17-56594326-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6703.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-56594326-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOG	NM_005450.6	c.103C>T	p.Pro35Ser	missense_variant	Exon 1 of 1	ENST00000332822.6	NP_005441.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOG	ENST00000332822.6	c.103C>T	p.Pro35Ser	missense_variant	Exon 1 of 1	6	NM_005450.6	ENSP00000328181.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

Brachydactyly type B2 Pathogenic:1

Jul 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Stapes ankylosis with broad thumbs and toes Pathogenic:1

Jul 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Proximal symphalangism 1A Pathogenic:1

Jul 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Nov 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro35 amino acid residue in NOG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10080184, 11545688). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NOG function (PMID: 17668388). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 6703). This missense change has been observed in individuals with clinical features of NOG-related symphalangism spectrum disorder (PMID: 11857750, 17668388, 18440889). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 35 of the NOG protein (p.Pro35Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.040
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.97		Gain of disorder (P = 0.1348);
MVP		0.98
MPC		1.9
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.79
gMVP		0.86

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: rs28937580; hg19: chr17-54671687;