rs2052465606

Variant names:

• chr17-56594227-G-T
• rs2052465606
• NM_005450.6:c.4G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005450.6(NOG):​c.4G>T​(p.Glu2*) variant causes a stop gained 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 (★). Synonymous variant affecting the same amino acid position (i.e. E2E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOG NM_005450.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.27
• Publications: 0 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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 50 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-56594227-G-T is Pathogenic according to our data. Variant chr17-56594227-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 986156.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005450.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOG	NM_005450.6	MANE Select	c.4G>T	p.Glu2*	stop_gained	Exon 1 of 1	NP_005441.1	Q13253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOG	ENST00000332822.6	TSL:6 MANE Select	c.4G>T	p.Glu2*	stop_gained	Exon 1 of 1	ENSP00000328181.4	Q13253

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1425028 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 706220

African (AFR) AF: 0.00 AC: 0 AN: 32642

American (AMR) AF: 0.00 AC: 0 AN: 39058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25398

East Asian (EAS) AF: 0.00 AC: 0 AN: 37714

South Asian (SAS) AF: 0.00 AC: 0 AN: 82868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094458

Other (OTH) AF: 0.00 AC: 0 AN: 59036

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		5.3
Vest4		0.68
GERP RS		3.0
Mutation Taster		=6/194	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: rs2052465606; hg19: chr17-54671588;