rs200361128

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/20 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

Publications

9 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 -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 Benign/Likely_benign. ClinVar VariationId is 167718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 200 XL,AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005634.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX3	NM_005634.3	MANE Select	c.157G>C	p.Val53Leu	missense	Exon 1 of 1	NP_005625.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SOX3	ENST00000370536.5	TSL:6 MANE Select	c.157G>C	p.Val53Leu	missense	Exon 1 of 1	ENSP00000359567.2
ENSG00000303910	ENST00000797999.1		n.105+1056C>G		intron	N/A
ENSG00000303910	ENST00000798000.1		n.158+1280C>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00411

AC:

464

AN:

112870

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00744

AC:

951

AN:

127771

AF XY:

0.00696

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 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

African (AFR)

AF:

0.000198

AC:

AN:

25311

American (AMR)

AF:

0.0219

AC:

682

AN:

31085

Ashkenazi Jewish (ASJ)

AF:

0.00768

AC:

145

AN:

18885

East Asian (EAS)

AF:

0.0120

AC:

333

AN:

27861

South Asian (SAS)

AF:

0.00161

AC:

AN:

51031

European-Finnish (FIN)

AF:

0.0146

AC:

554

AN:

38065

Middle Eastern (MID)

AF:

0.000763

AC:

AN:

3932

European-Non Finnish (NFE)

AF:

0.000931

AC:

771

AN:

828191

Other (OTH)

AF:

0.00391

AC:

176

AN:

44963

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

122

243

365

486

608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00411

AC:

464

AN:

112914

Hom.:

Cov.:

AF XY:

0.00570

AC XY:

200

AN XY:

35088

show subpopulations

African (AFR)

AF:

0.000257

AC:

AN:

31155

American (AMR)

AF:

0.0215

AC:

233

AN:

10857

Ashkenazi Jewish (ASJ)

AF:

0.00864

AC:

AN:

2662

East Asian (EAS)

AF:

0.0113

AC:

AN:

3540

South Asian (SAS)

AF:

0.00110

AC:

AN:

2725

European-Finnish (FIN)

AF:

0.0140

AC:

AN:

6281

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00115

AC:

AN:

53252

Other (OTH)

AF:

0.00518

AC:

AN:

1545

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.00222

Hom.:

Bravo

AF:

0.00524

ESP6500AA

AF:

0.000266

AC:

ESP6500EA

AF:

0.00137

AC:

ExAC

AF:

0.00414

AC:

482

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (3)

Abnormal brain morphology (1)

History of neurodevelopmental disorder (1)

Intellectual disability, X-linked, with panhypopituitarism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

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

PhyloP100

1.3

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

PromoterAI

-0.038

Neutral

(source)

Varity_R

0.29

gMVP

0.34

Mutation Taster

=98/2

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over