rs201101913

chrX-140504754-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005634.3(SOX3):c.307C>A(p.Pro103Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,172,491 control chromosomes in the GnomAD database, including 44 homozygotes. There are 920 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (17 hom., 459 hem., cov: 24)
  • Exomes 𝑓: 0.0017 (27 hom. 461 hem.)
• Consequence: SOX3 NM_005634.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.274

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020840764).
• BP6: Variant X-140504754-G-T is Benign according to our data. Variant chrX-140504754-G-T is described in ClinVar as [Benign]. Clinvar id is 95302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-140504754-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0151 (1707/112937) while in subpopulation AFR AF= 0.0504 (1571/31154). AF 95% confidence interval is 0.0484. There are 17 homozygotes in gnomad4. There are 459 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX3	NM_005634.3	c.307C>A	p.Pro103Thr	missense_variant	1/1	ENST00000370536.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX3	ENST00000370536.5	c.307C>A	p.Pro103Thr	missense_variant	1/1		NM_005634.3	P1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 1707 AN: 112894 Hom.: 17 Cov.: 24 AF XY: 0.0130 AC XY: 457 AN XY: 35040

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.000357

Gnomad OTH AF: 0.0137

GnomAD3 exomes AF: 0.00484 AC: 577 AN: 119122 Hom.: 12 AF XY: 0.00387 AC XY: 113 AN XY: 29174

Gnomad AFR exome AF: 0.0566

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000182

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000295

Gnomad OTH exome AF: 0.00259

GnomAD4 exome AF: 0.00166 AC: 1754 AN: 1059554 Hom.: 27 Cov.: 33 AF XY: 0.00136 AC XY: 461 AN XY: 337754

Gnomad4 AFR exome AF: 0.0509

Gnomad4 AMR exome AF: 0.00393

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000414

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000178

Gnomad4 OTH exome AF: 0.00419

GnomAD4 genome AF: 0.0151 AC: 1707 AN: 112937 Hom.: 17 Cov.: 24 AF XY: 0.0131 AC XY: 459 AN XY: 35093

Gnomad4 AFR AF: 0.0504

Gnomad4 AMR AF: 0.00869

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000357

Gnomad4 OTH AF: 0.0135

Alfa AF: 0.00613 Hom.: 40

Bravo AF: 0.0179

ESP6500AA AF: 0.0453 AC: 168

ESP6500EA AF: 0.000312 AC: 2

ExAC AF: 0.00448 AC: 518

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 09, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 31, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 13, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	13
Dann	Benign	0.92
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	0.87	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.11
Sift	Benign	0.081	T
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.062
MVP		0.21
ClinPred		0.0017	T
GERP RS		2.3
Varity_R		0.075
gMVP		0.64

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: rs201101913; hg19: chrX-139586919;