X-140503764-C-T

Variant names:

• chrX-140503764-C-T
• rs1178579710
• NM_005634.3:c.1297G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005634.3(SOX3):​c.1297G>A​(p.Ala433Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000945 in 1,057,694 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A433S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.5e-7 (0 hom. 1 hem.)
• Consequence: SOX3 NM_005634.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41381237).

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.1297G>A	p.Ala433Thr	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.1297G>A	p.Ala433Thr	missense	Exon 1 of 1	ENSP00000359567.2	P41225
	ENSG00000303910	ENST00000797999.1		n.21C>T		non_coding_transcript_exon	Exon 1 of 5
	ENSG00000303910	ENST00000798002.1		n.15C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.45e-7 AC: 1 AN: 1057694 Hom.: 0 Cov.: 31 AF XY: 0.00000295 AC XY: 1 AN XY: 339522

African (AFR) AF: 0.00 AC: 0 AN: 25914

American (AMR) AF: 0.00 AC: 0 AN: 31265

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18501

East Asian (EAS) AF: 0.00 AC: 0 AN: 29131

South Asian (SAS) AF: 0.00 AC: 0 AN: 49699

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29021

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2923

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 826561

Other (OTH) AF: 0.00 AC: 0 AN: 44679

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.38
Sift	Benign	0.079	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.33
MutPred		0.23		Gain of glycosylation at A433 (P = 0.0763)
MVP		0.58
ClinPred		0.90	D
GERP RS		2.7
Varity_R		0.32
gMVP		0.72
Mutation Taster		=55/45	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

dbSNP: rs1178579710; hg19: chrX-139585929;