chr6-21594734-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_003107.3(SOX4):​c.200T>C​(p.Met67Thr) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M67V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SOX4
NM_003107.3 missense

Scores

15
3
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.51
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-21594733-A-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.964
PP5
Variant 6-21594734-T-C is Pathogenic according to our data. Variant chr6-21594734-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3392529.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SOX4NM_003107.3 linkc.200T>C p.Met67Thr 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
SOX4ENST00000244745.4 linkc.200T>C p.Met67Thr missense_variant Exon 1 of 1 6 NM_003107.3 ENSP00000244745.1 Q06945
ENSG00000283480ENST00000637901.1 linkn.168+692A>G intron_variant Intron 1 of 2 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Coffin-Siris syndrome 10 Pathogenic:1
Sep 02, 2024
Institute of Human Genetics, Heidelberg University
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
33
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.99
D
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.94
D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H
PrimateAI
Pathogenic
0.95
D
PROVEAN
Pathogenic
-6.0
D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.91
MutPred
0.76
Loss of helix (P = 0.1299);
MVP
0.98
MPC
2.2
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.96
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-21594965; API