Genetic Variant SOX3:p.Ala246dup (chrX-140504323-A-AGCG) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_005634.3(SOX3):c.735_737dupCGC(p.Ala246dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000976 in 1,045,194 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.000068 ( 0 hom. 22 hem. )

Consequence

SOX3
NM_005634.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.162

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005634.3

BP6

Variant X-140504323-A-AGCG is Benign according to our data. Variant chrX-140504323-A-AGCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95305.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX3	NM_005634.3 link	c.735_737dupCGC	p.Ala246dup	disruptive_inframe_insertion	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.735_737dupCGC	p.Ala246dup	disruptive_inframe_insertion	Exon 1 of 1	6	NM_005634.3	ENSP00000359567.2		P41225

Frequencies

GnomAD3 genomes

AF:

0.000367

AC:

AN:

100807

Hom.:

Cov.:

AF XY:

0.000280

AC XY:

AN XY:

28609

show subpopulations

Gnomad AFR

AF:

0.0000739

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00266

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00629

Gnomad NFE

AF:

0.000142

Gnomad OTH

AF:

0.000760

GnomAD3 exomes

AF:

0.0000284

AC:

AN:

35250

Hom.:

AF XY:

0.000115

AC XY:

AN XY:

8724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000256

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000678

AC:

AN:

944350

Hom.:

Cov.:

AF XY:

0.0000734

AC XY:

AN XY:

299620

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000455

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000454

Gnomad4 OTH exome

AF:

0.000128

GnomAD4 genome

AF:

0.000377

AC:

AN:

100844

Hom.:

Cov.:

AF XY:

0.000279

AC XY:

AN XY:

28650

show subpopulations

Gnomad4 AFR

AF:

0.0000737

Gnomad4 AMR

AF:

0.00276

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000142

Gnomad4 OTH

AF:

0.000749

Alfa

AF:

0.000490

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Intellectual disability, X-linked, with panhypopituitarism

Uncertain:1

Apr 27, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SOX3-related disorder

Benign:1

Dec 21, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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