NM_000346.4:c.80C>A

Variant names:

• chr17-72121471-C-A
• rs1664736339
• NM_000346.4:c.80C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PP3_Moderate BP6_Moderate

The NM_000346.4(SOX9):​c.80C>A​(p.Ser27Tyr) variant causes a missense change. 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. S27S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SOX9 NM_000346.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.91
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• BP6: Variant 17-72121471-C-A is Benign according to our data. Variant chr17-72121471-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2150757.Status of the report is criteria_provided_single_submitter, 1 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.80C>A	p.Ser27Tyr	missense	Exon 1 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.80C>A	p.Ser27Tyr	missense	Exon 1 of 3	ENSP00000245479.2	P48436
	SOX9	ENST00000877559.1		c.80C>A	p.Ser27Tyr	missense	Exon 1 of 3	ENSP00000547618.1
	SOX9-AS1	ENST00000414600.1	TSL:3	n.96+20214G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Camptomelic dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.39
MVP		0.82
MPC		2.3
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		-0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.96
gMVP		0.75
Mutation Taster		=28/72	disease causing

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: rs1664736339; hg19: chr17-70117612;