chr17-56594151-G-A

Variant names:

• chr17-56594151-G-A
• rs183274390
• NM_005450.6:c.-73G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005450.6(NOG):​c.-73G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 1,338,074 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (73 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (83 hom.)
• Consequence: NOG NM_005450.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.413
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 17-56594151-G-A is Benign according to our data. Variant chr17-56594151-G-A is described in ClinVar as Benign. ClinVar VariationId is 1258795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

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.-73G>A		5_prime_UTR	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.-73G>A		5_prime_UTR	Exon 1 of 1	ENSP00000328181.4	Q13253

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2821 AN: 152078 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.0485

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00956

GnomAD4 exome AF: 0.00404 AC: 4790 AN: 1185888 Hom.: 83 Cov.: 17 AF XY: 0.00398 AC XY: 2342 AN XY: 588888

African (AFR) AF: 0.0545 AC: 1307 AN: 24000

American (AMR) AF: 0.00683 AC: 177 AN: 25916

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 203 AN: 20296

East Asian (EAS) AF: 0.0312 AC: 986 AN: 31614

South Asian (SAS) AF: 0.00410 AC: 269 AN: 65612

European-Finnish (FIN) AF: 0.0145 AC: 483 AN: 33420

Middle Eastern (MID) AF: 0.00810 AC: 29 AN: 3580

European-Non Finnish (NFE) AF: 0.000903 AC: 841 AN: 931022

Other (OTH) AF: 0.00982 AC: 495 AN: 50428

GnomAD4 genome AF: 0.0186 AC: 2837 AN: 152186 Hom.: 73 Cov.: 33 AF XY: 0.0192 AC XY: 1429 AN XY: 74408

African (AFR) AF: 0.0512 AC: 2128 AN: 41552

American (AMR) AF: 0.00856 AC: 131 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3468

East Asian (EAS) AF: 0.0489 AC: 252 AN: 5154

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4826

European-Finnish (FIN) AF: 0.0150 AC: 159 AN: 10602

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 67968

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00248 Hom.: 1

Bravo AF: 0.0199

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.97
PhyloP100		0.41
PromoterAI		-0.075	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs183274390; hg19: chr17-54671512; COSMIC: COSV60447612;