chr17-72122794-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_000346.4(SOX9):​c.507C>A​(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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

Scores

11
5
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.441
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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, 0.83

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SOX9NM_000346.4 linkuse as main transcriptc.507C>A p.His169Gln missense_variant 2/3 ENST00000245479.3 NP_000337.1 P48436

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SOX9ENST00000245479.3 linkuse as main transcriptc.507C>A p.His169Gln missense_variant 2/31 NM_000346.4 ENSP00000245479.2 P48436
SOX9-AS1ENST00000414600.1 linkuse as main transcriptn.96+18891G>T intron_variant 3
ENSG00000288605ENST00000628742.2 linkuse as main transcriptn.147-37749G>T intron_variant 5
ENSG00000288605ENST00000674828.1 linkuse as main transcriptn.304-77270G>T intron_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
36
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
0.40
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
0.80
D
LIST_S2
Uncertain
0.94
.;D
M_CAP
Pathogenic
0.73
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
0.91
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-70118935; API