rs1555629022

Variant names:

• chr17-72121643-C-G
• rs1555629022
• NM_000346.4:c.252C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-72121643-C-G
• chr17-72121643-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000346.4(SOX9):​c.252C>G​(p.Tyr84*) 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SOX9 NM_000346.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.64

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

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-72121643-C-G is Pathogenic according to our data. Variant chr17-72121643-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 468239.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX9	NM_000346.4	c.252C>G	p.Tyr84*	stop_gained	Exon 1 of 3	ENST00000245479.3	NP_000337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX9	ENST00000245479.3	c.252C>G	p.Tyr84*	stop_gained	Exon 1 of 3	1	NM_000346.4	ENSP00000245479.2
SOX9-AS1	ENST00000414600.1	n.96+20042G>C		intron_variant	Intron 1 of 1	3
ENSG00000288605	ENST00000628742.2	n.147-36598G>C		intron_variant	Intron 2 of 6	5
ENSG00000288605	ENST00000674828.1	n.304-76119G>C		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Camptomelic dysplasia Pathogenic:1

Sep 01, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal at codon 84 (p.Tyr84*) of the SOX9 gene. It is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in SOX9 are known to be pathogenic (PMID: 9002675). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.92
GERP RS		3.4

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: rs1555629022; hg19: chr17-70117784;