X-140503796-C-T

Variant names:

• chrX-140503796-C-T
• NM_005634.3:c.1265G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_005634.3(SOX3):​c.1265G>A​(p.Arg422His) variant causes a missense change. The variant allele was found at a frequency of 0.0000368 in 1,061,186 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000037 (0 hom. 9 hem.)
• Consequence: SOX3 NM_005634.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14
• 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 -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 9 XL,AR,AD gene

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.1265G>A	p.Arg422His	missense	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.1265G>A	p.Arg422His	missense	Exon 1 of 1	ENSP00000359567.2	P41225
	ENSG00000303910	ENST00000797999.1		n.53C>T		non_coding_transcript_exon	Exon 1 of 5
	ENSG00000303910	ENST00000798002.1		n.47C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000368 AC: 39 AN: 1061186 Hom.: 0 Cov.: 32 AF XY: 0.0000262 AC XY: 9 AN XY: 343414

African (AFR) AF: 0.0000385 AC: 1 AN: 25979

American (AMR) AF: 0.00 AC: 0 AN: 31441

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18659

East Asian (EAS) AF: 0.00 AC: 0 AN: 29185

South Asian (SAS) AF: 0.00 AC: 0 AN: 50480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3049

European-Non Finnish (NFE) AF: 0.0000458 AC: 38 AN: 829294

Other (OTH) AF: 0.00 AC: 0 AN: 44861

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, X-linked, with panhypopituitarism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.46
MutPred		0.41		Loss of methylation at R422 (P = 0.0116)
MVP		0.26
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.54
gMVP		0.78
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

hg19: chrX-139585961; COSMIC: COSV65167958;