chr12-23536546-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP5_Moderate

The NM_006940.6(SOX5):​c.1895C>A​(p.Thr632Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SOX5
NM_006940.6 missense

Scores

6
10
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 9.98
Variant links:
Genes affected
SOX5 (HGNC:11201): (SRY-box transcription factor 5) This 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. The encoded protein may play a role in chondrogenesis. A pseudogene of this gene is located on chromosome 8. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SOX5. . Gene score misZ 3.1513 (greater than the threshold 3.09). Trascript score misZ 3.799 (greater than threshold 3.09). GenCC has associacion of gene with Lamb-Shaffer syndrome, developmental and speech delay due to SOX5 deficiency.
PP5
Variant 12-23536546-G-T is Pathogenic according to our data. Variant chr12-23536546-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431148.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SOX5NM_006940.6 linkuse as main transcriptc.1895C>A p.Thr632Asn missense_variant 14/15 ENST00000451604.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SOX5ENST00000451604.7 linkuse as main transcriptc.1895C>A p.Thr632Asn missense_variant 14/151 NM_006940.6 A1P35711-1

Frequencies

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

ClinVar

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

Submissions by phenotype

Lamb-Shaffer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGroupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de ParisJan 06, 2017autism with no language; tall stature; macrocephaly -
Intellectual disability Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingInstitute for Human Genetics, University Hospital EssenAug 05, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Uncertain
0.058
T
BayesDel_noAF
Benign
-0.15
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
.;.;D;T;.;.;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
D;D;D;D;.;.;D;D
M_CAP
Benign
0.018
T
MetaRNN
Uncertain
0.67
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.15
T
MutationAssessor
Uncertain
2.9
.;.;M;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-4.8
D;D;D;D;D;.;D;D
REVEL
Uncertain
0.46
Sift
Uncertain
0.0010
D;D;D;D;D;.;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;.;D;D
Polyphen
0.99, 1.0, 1.0
.;D;D;.;D;D;D;.
Vest4
0.61
MutPred
0.33
.;.;Gain of catalytic residue at P627 (P = 0);.;.;.;.;.;
MVP
0.73
MPC
3.0
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.81
gMVP
0.90

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.

Other links and lift over

dbSNP: rs1135401816; hg19: chr12-23689480; API