17-72122794-C-G

Position:

• chr17-72122794-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_000346.4(SOX9):​c.507C>G​(p.His169Gln) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H169P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX9 NM_000346.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 0.441

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a DNA_binding_region HMG box (size 68) in uniprot entity SOX9_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_000346.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829
• PP5: Variant 17-72122794-C-G is Pathogenic according to our data. Variant chr17-72122794-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235914.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX9	NM_000346.4	c.507C>G	p.His169Gln	missense_variant	2/3	ENST00000245479.3	NP_000337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX9	ENST00000245479.3	c.507C>G	p.His169Gln	missense_variant	2/3	1	NM_000346.4	ENSP00000245479.2
SOX9-AS1	ENST00000414600.1	n.96+18891G>C		intron_variant		3
ENSG00000288605	ENST00000628742.2	n.147-37749G>C		intron_variant		5
ENSG00000288605	ENST00000674828.1	n.304-77270G>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Camptomelic dysplasia Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2023	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the SOX9 protein (p.His169Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of campomelic dysplasia (PMID: 24038782; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 235914). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOX9 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SOX9 function (PMID: 24038782). This variant disrupts the p.His169 amino acid residue in SOX9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19033726, 24038782). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 03, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 11, 2019	- -

not provided Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2023	Reported in an individual with cleft palate, campomelia, scapular hypoplasia, scoliosis, short trunk, mild bowing of long bones of lower limbs, and hypoplastic patellae; the variant was inherited from the mother with mild skeletal findings (Matsushita et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect with reduced transactivation capacity of the protein (Matsushita et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28965976, 19033726, 24038782) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2016	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 14, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.507C>G (p.H169Q) alteration is located in coding exon 2 of the SOX9 gene. This alteration results from a C to G substitution at nucleotide position 507, causing the histidine (H) at amino acid position 169 to be replaced by a glutamine (Q). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the SOX9 c.507C>G alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration was reported in a mother and son with an overlapping phenotype of mild campomelic dysplasia and small patella syndrome (Matsushita, 2013). The proband had cleft soft palate, developed scoliosis at age 7, and bilateral genu valgum deformities. He had a broad nasal bridge, disproportionate short trunk, asymmetric small scapulae, anteverted nares, and micrognathia. Skeletal surveys of the proband showed narrow iliac wings, defective iscio-pubic ossification, elongated femoral necks, hypoplastic lesser trochanter, and mild bowing of the long tubular bones of the lower limbs. The mother had proportionate normal stature, small patellae, and mild recurvatum of both knees (Matsushita, 2013). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.H169 amino acid is conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration:_x000D_ _x000D_ Using a luciferase assay in COS7 cells transiently expressing the mutation, Matsushita et al. (2013) found significantly reduced transactivation activity of the mutant protein at 46% of WT activity. They propose that the mutant retains some residual transactivation capacity for SOX9-responsive regulatory regions, explaining why some patients have relatively mild disease. The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.H169Q alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.6	D;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.027	D;.
Polyphen		0.051	B;B
Vest4		0.97
MutPred		0.44		Gain of MoRF binding (P = 0.0923);Gain of MoRF binding (P = 0.0923);
MVP		0.99
MPC		0.90
ClinPred		0.90	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98

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: rs2229989; hg19: chr17-70118935;