Variant 17-72122780-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000346.4(SOX9):c.493C>T(p.His165Tyr) variant causes a missense change involving the alteration of a 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H165Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SOX9
NM_000346.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.70

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]

SOX9 links:

SOX9-AS1 (HGNC:):

SOX9-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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, 0.969

PP5

Variant 17-72122780-C-T is Pathogenic according to our data. Variant chr17-72122780-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2513.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX9	NM_000346.4 linkuse as main transcript	c.493C>T	p.His165Tyr	missense_variant	2/3	ENST00000245479.3	NP_000337.1	P48436

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SOX9	ENST00000245479.3 linkuse as main transcript	c.493C>T	p.His165Tyr	missense_variant	2/3	1	NM_000346.4	ENSP00000245479.2	P48436
SOX9-AS1	ENST00000414600.1 linkuse as main transcript	n.96+18905G>A		intron_variant		3
ENSG00000288605	ENST00000628742.2 linkuse as main transcript	n.147-37735G>A		intron_variant		5
ENSG00000288605	ENST00000674828.1 linkuse as main transcript	n.304-77256G>A		intron_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Acampomelic campomelic dysplasia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

1.9

L;L

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.5

D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

0.96

D;D

Vest4

0.93

MutPred

0.85

Gain of phosphorylation at H165 (P = 0.067);Gain of phosphorylation at H165 (P = 0.067);

MVP

0.99

MPC

1.8

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over