6-21594727-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_003107.3(SOX4):​c.193G>A​(p.Ala65Thr) 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SOX4
NM_003107.3 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.34
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 Likely_pathogenic. Variant got 8 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, 0.987

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SOX4NM_003107.3 linkc.193G>A p.Ala65Thr 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.193G>A p.Ala65Thr missense_variant Exon 1 of 1 6 NM_003107.3 ENSP00000244745.1 Q06945
ENSG00000283480ENST00000637901.1 linkn.168+699C>T intron_variant Intron 1 of 2 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1443142
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
715854
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.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Coffin-Siris syndrome 10 Uncertain:1
Sep 23, 2020
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.3
H
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-4.0
D
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.87
MutPred
0.89
Gain of disorder (P = 0.1475);
MVP
0.99
MPC
2.1
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.82
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: chr6-21594958; API