rs104894602

Variant names:

• chr17-56594888-A-G
• rs104894602
• NM_005450.6:c.665A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-56594888-A-G
• chr17-56594888-A-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_005450.6(NOG):​c.665A>G​(p.Tyr222Cys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y222D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOG NM_005450.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.03
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• multiple synostoses syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• NOG-related symphalangism spectrum disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• brachydactyly type B2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• multiple synostoses syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• proximal symphalangism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• stapes ankylosis with broad thumbs and toes

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tarsal-carpal coalition syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr17-56594887-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6692.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 1.318 (below the threshold of 3.09). Trascript score misZ: 1.4011 (below the threshold of 3.09). GenCC associations: The gene is linked to stapes ankylosis with broad thumbs and toes, multiple synostoses syndrome, brachydactyly type B2, proximal symphalangism, tarsal-carpal coalition syndrome, multiple synostoses syndrome 1, NOG-related symphalangism spectrum disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 17-56594888-A-G is Pathogenic according to our data. Variant chr17-56594888-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOG	NM_005450.6	c.665A>G	p.Tyr222Cys	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.665A>G	p.Tyr222Cys	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

Alfa AF: 0.00108 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 16, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12478285, 31694554, 17245852, 7557985, 21538686, 22288654, 26211601, 29159868, 26994744, 11545688, 32478388, 10080184) -

Oct 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 222 of the NOG protein (p.Tyr222Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of NOG-related conditions (PMID: 10080184, 11545688). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6691). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Tarsal-carpal coalition syndrome Pathogenic:1

Sep 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Proximal symphalangism 1A Pathogenic:1

Mar 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.90
Sift	Benign	0.038	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.79	P
Vest4		0.85
MutPred		0.98		Gain of disorder (P = 0.0063);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.93
gMVP		0.98
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894602; hg19: chr17-54672249;