chr12-23536577-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP5

The NM_006940.6(SOX5):​c.1864G>A​(p.Asp622Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SOX5
NM_006940.6 missense

Scores

2
11
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 4.99
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 Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a DNA_binding_region HMG box (size 68) in uniprot entity SOX5_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) in NM_006940.6
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 12-23536577-C-T is Pathogenic according to our data. Variant chr12-23536577-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2500347.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SOX5NM_006940.6 linkuse as main transcriptc.1864G>A p.Asp622Asn missense_variant 14/15 ENST00000451604.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SOX5ENST00000451604.7 linkuse as main transcriptc.1864G>A p.Asp622Asn missense_variant 14/151 NM_006940.6 A1P35711-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461834
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727230
show subpopulations
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2024SOX5: PM1, PM2, PP2, PP3 -
Lamb-Shaffer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterFeb 09, 2023_x000D_ Criteria applied: PM1, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
.;.;D;T;.;.;.;.
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.85
D;D;D;D;.;.;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.50
T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Benign
1.1
.;.;L;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-0.34
N;N;N;N;N;.;N;N
REVEL
Uncertain
0.50
Sift
Benign
0.62
T;T;T;T;T;.;T;T
Sift4G
Benign
0.39
T;T;T;T;T;.;T;T
Polyphen
1.0, 0.047, 0.97
.;D;B;.;D;D;D;.
Vest4
0.42
MutPred
0.53
.;.;Gain of catalytic residue at P627 (P = 0);.;.;.;.;.;
MVP
0.89
MPC
2.7
ClinPred
0.80
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.15
gMVP
0.94

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: chr12-23689511; API