NM_000346.4:c.1320C>G

Variant names:

• chr17-72124177-C-G
• rs80338688
• NM_000346.4:c.1320C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_000346.4(SOX9):​c.1320C>G​(p.Tyr440*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★★). ClinVar reports functional evidence for this variant: "SCV005876515: Functional analyses of the variant protein demonstrate reduced but not eliminated transactivation activity (Au 2023, Pop 2005, Wagner 1994), suggesting this may be a hypomorphic variant with potential combined haploinsufficient and dominant-negative mechanisms. PMID:36584300. Hageman RM et al. Mutation analysis of the SOX9 gene in a patient with campomelic dysplasia. Hum Mutat. 1998" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y440Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX9 NM_000346.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: -0.0730
• Publications: 16 publications found

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:49321): (SOX9 antisense RNA 1)

ENSG00000288605 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 10 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005876515: Functional analyses of the variant protein demonstrate reduced but not eliminated transactivation activity (Au 2023, Pop 2005, Wagner 1994), suggesting this may be a hypomorphic variant with potential combined haploinsufficient and dominant-negative mechanisms. PMID: 36584300. Hageman RM et al. Mutation analysis of the SOX9 gene in a patient with campomelic dysplasia. Hum Mutat. 1998;Suppl 1:S112-3. PMID: 9452058. Meyer J et al. Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations. Hum Mol Genet. 1997 Jan;6(1):91-8. PMID: 9002675. Pop R et al. A homozygous nonsense mutation in SOX9 in the dominant disorder campomelic dysplasia: a case of mitotic gene conversion. Hum Genet. 2005 Jun;117(1):43-53. PMID: 15806394. Scocchia A et al. Diagnostic utility of next-generation sequencing-based panel testing in 543 patients with suspected skeletal dysplasia. Orphanet J Rare Dis. 2021 Oct 9;16(1):412. PMID: 34627339. Wagner T et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell. 1994 Dec 16;79(6):1111-20. PMID: 8001137.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-72124177-C-G is Pathogenic according to our data. Variant chr17-72124177-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000346.4. 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
	SOX9	NM_000346.4	MANE Select	c.1320C>G	p.Tyr440*	stop_gained	Exon 3 of 3	NP_000337.1	P48436

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX9	ENST00000245479.3	TSL:1 MANE Select	c.1320C>G	p.Tyr440*	stop_gained	Exon 3 of 3	ENSP00000245479.2	P48436
	SOX9	ENST00000877559.1		c.1485C>G	p.Tyr495*	stop_gained	Exon 3 of 3	ENSP00000547618.1
	SOX9-AS1	ENST00000414600.1	TSL:3	n.96+17508G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL (1)
1	-	-	Connective tissue disorder (1)
-	-	-	Camptomelic dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.52	D
PhyloP100		-0.073
Vest4		0.92
GERP RS		2.2
Mutation Taster		=0/200	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: rs80338688; hg19: chr17-70120318;