rs200361128

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005634.3(SOX3):c.157G>C(p.Val53Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,182,238 control chromosomes in the GnomAD database, including 12 homozygotes. There are 1,075 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 1 hom., 200 hem., cov: 24)

Exomes 𝑓: 0.0026 ( 11 hom. 875 hem. )

Consequence

SOX3
NM_005634.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:11

Conservation

PhyloP100: 1.33

Variant links:

Genes affected

SOX3 (HGNC:11199): (SRY-box transcription factor 3) 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. Mutations in this gene have been associated with X-linked cognitive disability with growth hormone deficiency. [provided by RefSeq, Jul 2008]

SOX3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046165287).

BP6

Variant X-140504904-C-G is Benign according to our data. Variant chrX-140504904-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 167718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-140504904-C-G is described in Lovd as [Pathogenic]. Variant chrX-140504904-C-G is described in Lovd as [Benign]. Variant chrX-140504904-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00411 (464/112914) while in subpopulation AMR AF= 0.0215 (233/10857). AF 95% confidence interval is 0.0192. There are 1 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 200 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX3	NM_005634.3 link	c.157G>C	p.Val53Leu	missense_variant	Exon 1 of 1	ENST00000370536.5	NP_005625.2	P41225

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX3	ENST00000370536.5 link	c.157G>C	p.Val53Leu	missense_variant	Exon 1 of 1	6	NM_005634.3	ENSP00000359567.2		P41225

Frequencies

GnomAD3 genomes

AF:

0.00411

AC:

464

AN:

112870

Hom.:

Cov.:

AF XY:

0.00574

AC XY:

201

AN XY:

35034

show subpopulations

Gnomad AFR

AF:

0.000257

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0214

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.0113

Gnomad SAS

AF:

0.00146

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.00524

GnomAD3 exomes

AF:

0.00744

AC:

951

AN:

127771

Hom.:

AF XY:

0.00696

AC XY:

282

AN XY:

40527

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0212

Gnomad ASJ exome

AF:

0.00850

Gnomad EAS exome

AF:

0.0125

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.0146

Gnomad NFE exome

AF:

0.00140

Gnomad OTH exome

AF:

0.00597

GnomAD4 exome

AF:

0.00257

AC:

2751

AN:

1069324

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

875

AN XY:

348464

show subpopulations

Gnomad4 AFR exome

AF:

0.000198

Gnomad4 AMR exome

AF:

0.0219

Gnomad4 ASJ exome

AF:

0.00768

Gnomad4 EAS exome

AF:

0.0120

Gnomad4 SAS exome

AF:

0.00161

Gnomad4 FIN exome

AF:

0.0146

Gnomad4 NFE exome

AF:

0.000931

Gnomad4 OTH exome

AF:

0.00391

GnomAD4 genome

AF:

0.00411

AC:

464

AN:

112914

Hom.:

Cov.:

AF XY:

0.00570

AC XY:

200

AN XY:

35088

show subpopulations

Gnomad4 AFR

AF:

0.000257

Gnomad4 AMR

AF:

0.0215

Gnomad4 ASJ

AF:

0.00864

Gnomad4 EAS

AF:

0.0113

Gnomad4 SAS

AF:

0.00110

Gnomad4 FIN

AF:

0.0140

Gnomad4 NFE

AF:

0.00115

Gnomad4 OTH

AF:

0.00518

Alfa

AF:

0.00222

Hom.:

Bravo

AF:

0.00524

ESP6500AA

AF:

0.000266

AC:

ESP6500EA

AF:

0.00137

AC:

ExAC

AF:

0.00414

AC:

482

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jun 29, 2014

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 18, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val53Leu variant in SOX3 is classified as benign because it has been identified in 2.1% of African/African American chromosomes, including 1 homozygote, in gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), which is higher than expected for a disease causing variant in SOX3. ACMG/AMP Criteria applied: BA1. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Abnormal brain morphology

Pathogenic:1

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

Intellectual disability, X-linked, with panhypopituitarism

Benign:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, with more than 300 hemizygous alleles in gnomAD v2 (MIM#300123). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

History of neurodevelopmental disorder

Benign:1

Dec 03, 2012

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: 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

0.18

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0046

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

0.81

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.45

REVEL

Benign

0.22

Sift

Pathogenic

0.0

Sift4G

Benign

0.66

Polyphen

0.0020

Vest4

0.054

MutPred

0.22

Loss of sheet (P = 0.007);

MVP

0.47

ClinPred

0.065

GERP RS

3.1

Varity_R

0.29

gMVP

0.34

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