rs794726924

Variant names:

• chrX-140504329-T-GGCG
• rs794726924
• NM_005634.3:c.732delAinsCGCC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP3 BP6 BP7

The NM_005634.3(SOX3):​c.732delAinsCGCC​(p.Ala244dup) variant causes a disruptive inframe insertion, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A244A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SOX3 NM_005634.3 disruptive_inframe_insertion, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.77
• Publications: 0 publications found

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

ENSG00000303910 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_005634.3
• BP6: Variant X-140504329-T-GGCG is Benign according to our data. Variant chrX-140504329-T-GGCG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193325.
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX3	NM_005634.3	c.732delAinsCGCC	p.Ala244dup	disruptive_inframe_insertion, synonymous_variant	Exon 1 of 1	ENST00000370536.5	NP_005625.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX3	ENST00000370536.5	c.732delAinsCGCC	p.Ala244dup	disruptive_inframe_insertion, synonymous_variant	Exon 1 of 1	6	NM_005634.3	ENSP00000359567.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

SOX3-related disorder Uncertain:1

Aug 28, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SOX3 c.732delinsCGCC variant is predicted to result in an in-frame deletion and insertion. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. An alternative variant resulting in the same duplication has been reported in 1 out of 74,592 allele in the population database (https://gnomad.broadinstitute.org/variant/X-139586506-A-AGCG?dataset=gnomad_r2_1). Alanine expansion in the PA tract has been reported in patients with growth hormone deficiency and hypopituitarism (Laumonnier et al. 2002. PubMed ID: 12428212; Woods et al. 2005. PubMed ID: 15800844; Blum et al. 2018. PubMed ID: 30266296). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Sep 15, 2014

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794726924; hg19: chrX-139586494;