X-140505047-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/18 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:10

Conservation

PhyloP100: -0.414

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 -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 [Likely_benign]. Clinvar id is 193320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-140505047-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd at 113 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX3	NM_005634.3 linkuse as main transcript	c.14G>A	p.Arg5Gln	missense_variant	1/1	ENST00000370536.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX3	ENST00000370536.5 linkuse as main transcript	c.14G>A	p.Arg5Gln	missense_variant	1/1		NM_005634.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00293

AC:

329

AN:

112177

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

113

AN XY:

34329

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

GnomAD3 exomes

AF:

0.00286

AC:

467

AN:

163377

Hom.:

AF XY:

0.00290

AC XY:

160

AN XY:

55159

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 SAS exome

AF:

0.00170

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

Gnomad4 AFR exome

AF:

0.000382

Gnomad4 AMR exome

AF:

0.000230

Gnomad4 ASJ exome

AF:

0.000207

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00213

Gnomad4 FIN exome

AF:

0.0145

Gnomad4 NFE exome

AF:

0.00326

Gnomad4 OTH exome

AF:

0.00216

GnomAD4 genome

AF:

0.00293

AC:

329

AN:

112223

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

113

AN XY:

34385

show subpopulations

Gnomad4 AFR

AF:

0.000291

Gnomad4 AMR

AF:

0.000932

Gnomad4 ASJ

AF:

0.000376

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000747

Gnomad4 FIN

AF:

0.0140

Gnomad4 NFE

AF:

0.00406

Gnomad4 OTH

AF:

0.000657

Alfa

AF:

0.00264

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 13, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 22, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 30, 2014	- -

SOX3-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2021

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 28, 2022

- -

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

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

MutationTaster

Benign

1.0

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

Varity_R

0.032

gMVP

0.18

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