12-23534419-C-T

Position:

chr12-23534419-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_006940.6(SOX5):c.2092G>A(p.Val698Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

SOX5
NM_006940.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.17

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]

SOX5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.11243448).

BP6

Variant 12-23534419-C-T is Benign according to our data. Variant chr12-23534419-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2498547.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000158 (24/152150) while in subpopulation SAS AF= 0.000415 (2/4820). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX5	NM_006940.6 linkuse as main transcript	c.2092G>A	p.Val698Met	missense_variant	15/15	ENST00000451604.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX5	ENST00000451604.7 linkuse as main transcript	c.2092G>A	p.Val698Met	missense_variant	15/15	1	NM_006940.6	A1	P35711-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251182

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000253

AC:

370

AN:

1461826

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

183

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000278

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000158

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000225

Hom.:

Bravo

AF:

0.000140

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000148

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

SOX5: PP2 -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;.;T;T;.;.;.;.

Eigen

Benign

-0.068

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

D;D;D;D;.;.;D;D

M_CAP

Benign

0.0040

MetaRNN

Benign

0.11

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

.;.;N;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.25

N;N;N;N;N;.;N;N

REVEL

Benign

0.097

Sift

Benign

0.14

T;D;T;T;D;.;T;T

Sift4G

Benign

0.38

T;T;T;T;T;.;T;T

Polyphen

0.11, 0.23, 0.22

.;B;B;.;B;B;B;.

Vest4

0.16

MVP

0.043

MPC

0.12

ClinPred

0.018

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.23

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