rs794726924

Positions:

• chrX-140504328-CT-CGGCG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP3 BP6

The NM_005634.3(SOX3):​c.732delinsCGCC​(p.Ala247dup) variant causes a inframe insertion 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).

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

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 Uncertain_significance. Variant got 0 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 id is 193325.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX3	NM_005634.3	c.732delinsCGCC	p.Ala247dup	inframe_insertion	1/1	ENST00000370536.5	NP_005625.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX3	ENST00000370536.5	c.732delinsCGCC	p.Ala247dup	inframe_insertion	1/1		NM_005634.3	ENSP00000359567	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 15, 2014

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs794726924; hg19: chrX-139586494;