rs587776541

chr17-72123592-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000346.4(SOX9):c.736dup(p.Gln246ProfsTer6) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX9 NM_000346.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.63

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)

ACMG classification

Verdict is Pathogenic. Variant got 11 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 35 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-72123592-G-GC is Pathogenic according to our data. Variant chr17-72123592-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 2509.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX9	NM_000346.4	c.736dup	p.Gln246ProfsTer6	frameshift_variant	3/3	ENST00000245479.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX9	ENST00000245479.3	c.736dup	p.Gln246ProfsTer6	frameshift_variant	3/3	1	NM_000346.4	P1
SOX9-AS1	ENST00000414600.1	n.96+18092_96+18093insG		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Campomelic dysplasia with autosomal sex reversal Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1996

- -

Camptomelic dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

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: rs587776541; hg19: chr17-70119733;