rs80338688

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-72124177-C-A
• chr17-72124177-C-G
• chr17-72124177-C-T

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>A​(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: "SCV000330099: Functional studies show that Y440X allows for some residual activity of the SOX9 protein (Meyer et al., 1997).". 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:2 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: SCV000330099: Functional studies show that Y440X allows for some residual activity of the SOX9 protein (Meyer et al., 1997).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-72124177-C-A is Pathogenic according to our data. Variant chr17-72124177-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 21163.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>A	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>A	p.Tyr440*	stop_gained	Exon 3 of 3	ENSP00000245479.2	P48436
	SOX9	ENST00000877559.1		c.1485C>A	p.Tyr495*	stop_gained	Exon 3 of 3	ENSP00000547618.1
	SOX9-AS1	ENST00000414600.1	TSL:3	n.96+17508G>T		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
1	-	-	Camptomelic dysplasia (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.51	D
PhyloP100		-0.073
Vest4		0.92
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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;