17-56594151-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 0.413

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 Benign. Variant got -14 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 id is 1258795.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOG	NM_005450.6	c.-73G>A		5_prime_UTR_variant	1/1	ENST00000332822.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOG	ENST00000332822.6	c.-73G>A		5_prime_UTR_variant	1/1		NM_005450.6	P1

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

Gnomad4 AFR exome AF: 0.0545

Gnomad4 AMR exome AF: 0.00683

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.0312

Gnomad4 SAS exome AF: 0.00410

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.000903

Gnomad4 OTH exome AF: 0.00982

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

Gnomad4 AFR AF: 0.0512

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.0489

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00248 Hom.: 1

Bravo AF: 0.0199

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 29, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	15
Dann	Benign	0.97

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