rs104894610

Positions:

• chr17-56594834-G-A
• chr17-56594834-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_005450.6(NOG):​c.611G>A​(p.Arg204Gln) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOG NM_005450.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.67

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 11 ACMG points.

• PM1: In a disulfide_bond (size 46) in uniprot entity NOGG_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) 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 chr17-56594834-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 17-56594834-G-A is Pathogenic according to our data. Variant chr17-56594834-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 375295.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr17-56594834-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOG	NM_005450.6	c.611G>A	p.Arg204Gln	missense_variant	1/1	ENST00000332822.6	NP_005441.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOG	ENST00000332822.6	c.611G>A	p.Arg204Gln	missense_variant	1/1		NM_005450.6	ENSP00000328181	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Symphalangism-brachydactyly syndrome;C1861305:Tarsal-carpal coalition syndrome;C1866656:Stapes ankylosis with broad thumbs and toes;C1969652:Brachydactyly type B2;C3714899:Proximal symphalangism 1A Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Clinical Genomics Laboratory, Stanford Medicine

May 06, 2020

The p.Arg204Gln variant in the NOG gene has been previously reported in 3 related individuals from 1 family with tarsal-carpal coalition syndrome. This variant co-segregated with disease in affected family members presenting with variable skeletal anomalies including proximal symphalangism and carpal and tarsal fusion (Das Bhowmik et al., 2018). The p.Arg204Gln variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Notably, a different amino acid change (p.Arg204Leu) has been previously reported at this residue, as well as amino acid changes at nearby residues (p.Leu203Pro, p.Trp205Cys), suggesting the p.Arg204Gln variant may occur in a mutational hotspot of the NOG gene. Computational tools predict that the p.Arg204Gln variant is deleterious; however, the accuracy of in silicoalgorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg204Gln variant as likely pathogenic for a NOG-related disorder in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2_Moderate; PM1_supporting; PM2; PP3] -

Tarsal-carpal coalition syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS

Jan 01, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 12, 2022

ClinVar contains an entry for this variant (Variation ID: 375295). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. This missense change has been observed in individual(s) with tarsal-carpal coalition syndrome (PMID: 29159868). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 204 of the NOG protein (p.Arg204Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.91		Loss of sheet (P = 0.0228);
MVP		0.99
MPC		2.0
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.91
gMVP		0.99

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: rs104894610; hg19: chr17-54672195;