X-140504934-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005634.3(SOX3):c.127G>A(p.Ala43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,198,480 control chromosomes in the GnomAD database, including 155 homozygotes. There are 1,328 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 74 hom., 655 hem., cov: 24)

Exomes 𝑓: 0.0025 ( 81 hom. 673 hem. )

Consequence

SOX3
NM_005634.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.579

Publications

10 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=0.0015605986).

BP6

Variant X-140504934-C-T is Benign according to our data. Variant chrX-140504934-C-T is described in ClinVar as Benign. ClinVar VariationId is 193322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX3	NM_005634.3 link	c.127G>A	p.Ala43Thr	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.127G>A	p.Ala43Thr	missense_variant	Exon 1 of 1	6	NM_005634.3	ENSP00000359567.2		P41225

Frequencies

GnomAD3 genomes

AF:

0.0226

AC:

2546

AN:

112841

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00940

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000366

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000131

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.00628

AC:

939

AN:

149416

AF XY:

0.00372

show subpopulations

Gnomad AFR exome

AF:

0.0859

Gnomad AMR exome

AF:

0.00390

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000128

Gnomad OTH exome

AF:

0.00437

GnomAD4 exome

AF:

0.00250

AC:

2711

AN:

1085592

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

673

AN XY:

355352

show subpopulations

African (AFR)

AF:

0.0848

AC:

2197

AN:

25893

American (AMR)

AF:

0.00446

AC:

152

AN:

34081

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19162

East Asian (EAS)

AF:

0.00

AC:

AN:

29032

South Asian (SAS)

AF:

0.000153

AC:

AN:

52247

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39150

Middle Eastern (MID)

AF:

0.00198

AC:

AN:

4034

European-Non Finnish (NFE)

AF:

0.000114

AC:

AN:

836424

Other (OTH)

AF:

0.00551

AC:

251

AN:

45569

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

137

274

410

547

684

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.0226

AC:

2548

AN:

112888

Hom.:

Cov.:

AF XY:

0.0187

AC XY:

655

AN XY:

35066

show subpopulations

African (AFR)

AF:

0.0772

AC:

2401

AN:

31091

American (AMR)

AF:

0.00939

AC:

102

AN:

10867

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2661

East Asian (EAS)

AF:

0.00

AC:

AN:

3539

South Asian (SAS)

AF:

0.000367

AC:

AN:

2723

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000131

AC:

AN:

53291

Other (OTH)

AF:

0.0242

AC:

AN:

1532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

180

269

359

449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00712

Hom.:

261

Bravo

AF:

0.0259

ESP6500AA

AF:

0.0695

AC:

265

ESP6500EA

AF:

0.000449

AC:

ExAC

AF:

0.00656

AC:

788

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 20, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 06, 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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Sep 29, 2015

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

0.063

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.49

CADD

Benign

4.8

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.24

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.34

PhyloP100

0.58

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.14

REVEL

Uncertain

0.29

Sift

Benign

0.31

Sift4G

Benign

0.34

Polyphen

0.0

Vest4

0.0040

MVP

0.27

ClinPred

0.0027

GERP RS

0.84

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.044

gMVP

0.14

Mutation Taster

=99/1

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

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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