NM_005450.6:c.31C>G

Variant names:

• chr17-56594254-C-G
• rs1214929623
• NM_005450.6:c.31C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005450.6(NOG):​c.31C>G​(p.Leu11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOG NM_005450.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31576174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOG	NM_005450.6	c.31C>G	p.Leu11Val	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.31C>G	p.Leu11Val	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

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.49	N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.27
Sift	Benign	0.89	T
Sift4G	Benign	0.46	T
Polyphen		0.0020	B
Vest4		0.28
MutPred		0.32		Gain of sheet (P = 0.0344);
MVP		0.53
MPC		0.77
ClinPred		0.11	T
GERP RS		3.7
Varity_R		0.14
gMVP		0.38

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: rs1214929623; hg19: chr17-54671615;