Variant chr6-21594732-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_003107.3(SOX4):c.198C>A(p.Phe66Leu) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SOX4
NM_003107.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 3.02

Variant links:

Genes affected

SOX4 (HGNC:11200): (SRY-box transcription factor 4) This intronless gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins, such as syndecan binding protein (syntenin). The protein may function in the apoptosis pathway leading to cell death as well as to tumorigenesis and may mediate downstream effects of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in bone development. The solution structure has been resolved for the HMG-box of a similar mouse protein. [provided by RefSeq, Jul 2008]

SOX4 links:

ENSG00000283480 (HGNC:):

ENSG00000283480 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a DNA_binding_region HMG box (size 68) in uniprot entity SOX4_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_003107.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

PP5

Variant 6-21594732-C-A is Pathogenic according to our data. Variant chr6-21594732-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548142.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-21594732-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX4	NM_003107.3 link	c.198C>A	p.Phe66Leu	missense_variant	Exon 1 of 1	ENST00000244745.4	NP_003098.1	Q06945

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX4	ENST00000244745.4 link	c.198C>A	p.Phe66Leu	missense_variant	Exon 1 of 1	6	NM_003107.3	ENSP00000244745.1		Q06945
ENSG00000283480	ENST00000637901.1 link	n.168+694G>T		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443688

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716158

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, mild

Pathogenic:1

Feb 20, 2019

Medical Genetics Lab, Policlinico S. Orsola.Malpighi

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Phe66Leu variant is de novo, it is absent in population databases and it involves a higly conserved residue in the HMG box DNA-binding domain of the protein. Three further patients were identified with de novo missense variants affecting the HMG box DNA-binding domain of SOX4. Intellectual disability and similar facial dysmorphisms were present in all four. Functional assays demonstrated that SOX4 proteins carrying these four variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. -

Coffin-Siris syndrome 10

Pathogenic:1

Feb 02, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Developmental delay;C3714756:Intellectual disability;na:Mild facial and digital morphological abnormalities

Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.99

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.90

Sift

Benign

0.032

Sift4G

Uncertain

0.044

Polyphen

0.99

Vest4

0.86

MutPred

0.82

Loss of helix (P = 0.0376);

MVP

0.99

MPC

1.7

ClinPred

1.0

GERP RS

2.3

Varity_R

0.78

gMVP

1.0

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