X-140505047-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005634.3(SOX3):c.14G>A(p.Arg5Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,203,988 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,306 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0029 ( 0 hom., 113 hem., cov: 23)

Exomes 𝑓: 0.0032 ( 7 hom. 1193 hem. )

Consequence

SOX3
NM_005634.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.414

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

46,XX sex reversal 3
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
intellectual disability, X-linked, with panhypopituitarism
Inheritance: XL Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, G2P
panhypopituitarism, X-linked
Inheritance: XL Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder
Inheritance: XL Classification: MODERATE Submitted by: ClinGen
46,XX sex reversal 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
septooptic dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
panhypopituitarism
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
X-linked congenital generalized hypertrichosis
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked intellectual disability with isolated growth hormone deficiency
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
46,XX ovotesticular disorder of sex development
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

SOX3 links:

ENSG00000303910 (HGNC:):

ENSG00000303910 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027991235).

BP6

Variant X-140505047-C-T is Benign according to our data. Variant chrX-140505047-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 113 XL,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX3	NM_005634.3 link	c.14G>A	p.Arg5Gln	missense_variant	Exon 1 of 1	ENST00000370536.5	NP_005625.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX3	ENST00000370536.5 link	c.14G>A	p.Arg5Gln	missense_variant	Exon 1 of 1	6	NM_005634.3	ENSP00000359567.2

Frequencies

GnomAD3 genomes

AF:

0.00293

AC:

329

AN:

112177

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000292

Gnomad AMI

AF:

0.00588

Gnomad AMR

AF:

0.000933

Gnomad ASJ

AF:

0.000376

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000745

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00406

Gnomad OTH

AF:

0.000665

GnomAD2 exomes

AF:

0.00286

AC:

467

AN:

163377

AF XY:

0.00290

show subpopulations

Gnomad AFR exome

AF:

0.000469

Gnomad AMR exome

AF:

0.000113

Gnomad ASJ exome

AF:

0.000419

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0145

Gnomad NFE exome

AF:

0.00291

Gnomad OTH exome

AF:

0.00168

GnomAD4 exome

AF:

0.00325

AC:

3547

AN:

1091765

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

1193

AN XY:

358327

show subpopulations

African (AFR)

AF:

0.000382

AC:

AN:

26196

American (AMR)

AF:

0.000230

AC:

AN:

34847

Ashkenazi Jewish (ASJ)

AF:

0.000207

AC:

AN:

19306

East Asian (EAS)

AF:

0.00

AC:

AN:

29785

South Asian (SAS)

AF:

0.00213

AC:

113

AN:

52989

European-Finnish (FIN)

AF:

0.0145

AC:

575

AN:

39556

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.00326

AC:

2733

AN:

839113

Other (OTH)

AF:

0.00216

AC:

AN:

45855

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

148

297

445

594

742

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00293

AC:

329

AN:

112223

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

113

AN XY:

34385

show subpopulations

African (AFR)

AF:

0.000291

AC:

AN:

30910

American (AMR)

AF:

0.000932

AC:

AN:

10733

Ashkenazi Jewish (ASJ)

AF:

0.000376

AC:

AN:

2663

East Asian (EAS)

AF:

0.00

AC:

AN:

3514

South Asian (SAS)

AF:

0.000747

AC:

AN:

2676

European-Finnish (FIN)

AF:

0.0140

AC:

AN:

6142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00406

AC:

216

AN:

53168

Other (OTH)

AF:

0.000657

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00246

Hom.:

122

Bravo

AF:

0.00153

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00173

AC:

ESP6500AA

AF:

0.000263

AC:

ESP6500EA

AF:

0.00301

AC:

ExAC

AF:

0.00315

AC:

381

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 13, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Sep 22, 2016

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: 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. -

Oct 30, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SOX3-related disorder

Benign:1

Apr 27, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Panhypopituitarism, X-linked;C2678223:Intellectual disability, X-linked, with panhypopituitarism

Benign:1

Jan 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

2.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0028

MetaSVM

Uncertain

-0.0061

MutationAssessor

Benign

0.55

PhyloP100

-0.41

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.44

REVEL

Benign

0.22

Sift

Benign

0.097

Sift4G

Benign

0.075

Polyphen

0.0

Vest4

0.022

MVP

0.21

ClinPred

0.0020

GERP RS

-1.6

PromoterAI

-0.093

Neutral

(source)

Varity_R

0.032

gMVP

0.18

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over