17-72122941-G-C

Variant names:

• chr17-72122941-G-C
• rs747366415
• NM_000346.4:c.654G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000346.4(SOX9):​c.654G>C​(p.Met218Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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 Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M218V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX9 NM_000346.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.47
• 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.

• PM1: In a region_of_interest Disordered (size 113) in uniprot entity SOX9_HUMAN there are 22 pathogenic changes around while only 6 benign (79%) in NM_000346.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23832121).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX9	NM_000346.4	c.654G>C	p.Met218Ile	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.654G>C	p.Met218Ile	missense_variant	Exon 2 of 3	1	NM_000346.4	ENSP00000245479.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;D
Eigen	Benign	0.039
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	.;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		6.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.28
Sift	Benign	0.22	T;.
Sift4G	Benign	0.30	T;.
Polyphen		0.0	B;B
Vest4		0.20
MutPred		0.21		Gain of glycosylation at S219 (P = 0.0738);Gain of glycosylation at S219 (P = 0.0738);
MVP		0.65
MPC		0.97
ClinPred		0.93	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.38
Mutation Taster		=70/30	polymorphism

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: rs747366415; hg19: chr17-70119082;