X-140503984-AGCTGCGGCCGCGGCGGTG-A

Variant names:

• chrX-140503984-AGCTGCGGCCGCGGCGGTG-A
• rs1200616062
• NM_005634.3:c.1059_1076delCACCGCCGCGGCCGCAGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_005634.3(SOX3):​c.1059_1076delCACCGCCGCGGCCGCAGC​(p.Thr354_Ala359del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000197 in 1,015,438 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000093 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000011 (0 hom. 0 hem.)
• Consequence: SOX3 NM_005634.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.71
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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.

• BP3: Nonframeshift variant in repetitive region in NM_005634.3

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005634.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX3	NM_005634.3	MANE Select	c.1059_1076delCACCGCCGCGGCCGCAGC	p.Thr354_Ala359del	disruptive_inframe_deletion	Exon 1 of 1	NP_005625.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX3	ENST00000370536.5	TSL:6 MANE Select	c.1059_1076delCACCGCCGCGGCCGCAGC	p.Thr354_Ala359del	disruptive_inframe_deletion	Exon 1 of 1	ENSP00000359567.2	P41225
	ENSG00000303910	ENST00000797999.1		n.105+139_105+156delTGCGGCCGCGGCGGTGGC		intron	N/A
	ENSG00000303910	ENST00000798000.1		n.158+363_158+380delTGCGGCCGCGGCGGTGGC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000932 AC: 1 AN: 107281 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000194

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000110 AC: 1 AN: 908157 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 277065

African (AFR) AF: 0.00 AC: 0 AN: 19420

American (AMR) AF: 0.00 AC: 0 AN: 10033

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13784

East Asian (EAS) AF: 0.00 AC: 0 AN: 22051

South Asian (SAS) AF: 0.00 AC: 0 AN: 29176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22095

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2373

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 751744

Other (OTH) AF: 0.0000267 AC: 1 AN: 37481

GnomAD4 genome AF: 0.00000932 AC: 1 AN: 107281 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 31247

African (AFR) AF: 0.00 AC: 0 AN: 29484

American (AMR) AF: 0.00 AC: 0 AN: 10399

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2579

East Asian (EAS) AF: 0.00 AC: 0 AN: 3267

South Asian (SAS) AF: 0.00 AC: 0 AN: 2503

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.0000194 AC: 1 AN: 51459

Other (OTH) AF: 0.00 AC: 0 AN: 1458

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	SOX3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7

Splicing

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

Other links and lift over

dbSNP: rs1200616062; hg19: chrX-139586149;