17-72124037-C-T

Position:

• chr17-72124037-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000346.4(SOX9):​c.1180C>T​(p.Arg394*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SOX9 NM_000346.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.126

Genes affected

SOX9 (HGNC:11204): (SRY-box transcription factor 9) The protein encoded by this gene recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Muellerian hormone (AMH) gene. Deficiencies lead to the skeletal malformation syndrome campomelic dysplasia, frequently with sex reversal. [provided by RefSeq, Jul 2008]

SOX9-AS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 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. Fraction of 0.229 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-72124037-C-T is Pathogenic according to our data. Variant chr17-72124037-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 373101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-72124037-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX9	NM_000346.4	c.1180C>T	p.Arg394*	stop_gained	3/3	ENST00000245479.3	NP_000337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX9	ENST00000245479.3	c.1180C>T	p.Arg394*	stop_gained	3/3	1	NM_000346.4	ENSP00000245479.2
SOX9-AS1	ENST00000414600.1	n.96+17648G>A		intron_variant		3
ENSG00000288605	ENST00000628742.2	n.147-38992G>A		intron_variant		5
ENSG00000288605	ENST00000674828.1	n.304-78513G>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458232 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 725078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Camptomelic dysplasia Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 20, 2017	Several different truncations downstream of this variant (p.Glu400*, p.Gln401*, p.Tyr432*, etc) have been reported in individuals affected with campomelic dysplasia  (PMID: 9002675, 21614988, 27899157). This suggests that deletion of this region of the SOX9 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. This variant has been reported to be de novo in an individual affected with skeletal dysplasia (http://www.softgenetics.com/PDF/AMP2013_MJ-Basehore.pdf). ClinVar contains an entry for this variant (Variation ID: 373101). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the SOX9 gene (p.Arg394*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 116 amino acids of the SOX9 protein. -
Pathogenic, no assertion criteria provided	clinical testing	Krakow/Cohn Lab, University of California, Los Angeles	Jul 01, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 20, 2024

Nonsense variant predicted to result in protein truncation, as the last 116 amino acid(s) are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31389106, 36467484, 27248473) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.79	D
Vest4		0.94
GERP RS		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1057518216; hg19: chr17-70120178; COSMIC: COSV55430247; COSMIC: COSV55430247;