chr17-72122749-C-A

Variant names:

• chr17-72122749-C-A
• NM_000346.4:c.462C>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PP3_Strong

The NM_000346.4(SOX9):​c.462C>A​(p.Phe154Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX9 NM_000346.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.374

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.

• PS1: Transcript NM_000346.4 (SOX9) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX9	NM_000346.4	c.462C>A	p.Phe154Leu	missense_variant	Exon 2 of 3	ENST00000245479.3	NP_000337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX9	ENST00000245479.3	c.462C>A	p.Phe154Leu	missense_variant	Exon 2 of 3	1	NM_000346.4	ENSP00000245479.2
SOX9-AS1	ENST00000414600.1	n.96+18936G>T		intron_variant	Intron 1 of 1	3
ENSG00000288605	ENST00000628742.2	n.147-37704G>T		intron_variant	Intron 2 of 6	5
ENSG00000288605	ENST00000674828.1	n.304-77225G>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.5	D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.81	P;P
Vest4		0.93
MutPred		0.83		Gain of ubiquitination at K151 (P = 0.0545);Gain of ubiquitination at K151 (P = 0.0545);
MVP		1.0
MPC		1.2
ClinPred		0.98	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-70118890;