rs200361128

Positions:

• chrX-140504904-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:11
• Conservation: PhyloP100: 1.33

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]

ACMG classification

Verdict is Benign. Variant got -13 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167718.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Likely_pathogenic=1}. Variant chrX-140504904-C-G is described in Lovd as [Pathogenic]. Variant chrX-140504904-C-G is described in Lovd as [Benign]. Variant chrX-140504904-C-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 200 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX3	NM_005634.3	c.157G>C	p.Val53Leu	missense_variant	1/1	ENST00000370536.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX3	ENST00000370536.5	c.157G>C	p.Val53Leu	missense_variant	1/1		NM_005634.3	P1

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 464 AN: 112870 Hom.: 1 Cov.: 24 AF XY: 0.00574 AC XY: 201 AN XY: 35034

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

GnomAD3 exomes AF: 0.00744 AC: 951 AN: 127771 Hom.: 5 AF XY: 0.00696 AC XY: 282 AN XY: 40527

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 SAS exome AF: 0.00186

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.: 11 Cov.: 33 AF XY: 0.00251 AC XY: 875 AN XY: 348464

Gnomad4 AFR exome AF: 0.000198

Gnomad4 AMR exome AF: 0.0219

Gnomad4 ASJ exome AF: 0.00768

Gnomad4 EAS exome AF: 0.0120

Gnomad4 SAS exome AF: 0.00161

Gnomad4 FIN exome AF: 0.0146

Gnomad4 NFE exome AF: 0.000931

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.00411 AC: 464 AN: 112914 Hom.: 1 Cov.: 24 AF XY: 0.00570 AC XY: 200 AN XY: 35088

Gnomad4 AFR AF: 0.000257

Gnomad4 AMR AF: 0.0215

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.0113

Gnomad4 SAS AF: 0.00110

Gnomad4 FIN AF: 0.0140

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00518

Alfa AF: 0.00222 Hom.: 44

Bravo AF: 0.00524

ESP6500AA AF: 0.000266 AC: 1

ESP6500EA AF: 0.00137 AC: 9

ExAC AF: 0.00414 AC: 482

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 18, 2023	The p.Val53Leu variant in SOX3 is classified as benign because it has been identified in 2.1% of African/African American chromosomes, including 1 homozygote, in gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), which is higher than expected for a disease causing variant in SOX3. ACMG/AMP Criteria applied: BA1. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 18, 2019	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

- -

Intellectual disability, X-linked, with panhypopituitarism Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 17, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of intellectual developmental disorder, X-linked, with isolated growth hormone deficiency, with more than 300 hemizygous alleles in gnomAD v2 (MIM#300123). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

History of neurodevelopmental disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2012

This alteration is classified as benign based on a combination of the following: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0046	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.66	T
Polyphen		0.0020	B
Vest4		0.054
MutPred		0.22		Loss of sheet (P = 0.007);
MVP		0.47
ClinPred		0.065	T
GERP RS		3.1
Varity_R		0.29
gMVP		0.34

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

Other links and lift over

dbSNP: rs200361128; hg19: chrX-139587069; COSMIC: COSV65168804;