NM_005634.3:c.1060A>C

Variant names:

• chrX-140504001-T-G
• NM_005634.3:c.1060A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005634.3(SOX3):​c.1060A>C​(p.Thr354Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000023 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SOX3 NM_005634.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.462
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13135037).

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.1060A>C	p.Thr354Pro	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.1060A>C	p.Thr354Pro	missense	Exon 1 of 1	ENSP00000359567.2	P41225
	ENSG00000303910	ENST00000797999.1		n.105+153T>G		intron	N/A
	ENSG00000303910	ENST00000798000.1		n.158+377T>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000230 AC: 2 AN: 868001 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 258497

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18181

American (AMR) AF: 0.00 AC: 0 AN: 7991

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12355

East Asian (EAS) AF: 0.00 AC: 0 AN: 20644

South Asian (SAS) AF: 0.00 AC: 0 AN: 25383

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2239

European-Non Finnish (NFE) AF: 0.00000276 AC: 2 AN: 724743

Other (OTH) AF: 0.00 AC: 0 AN: 35803

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.29	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.46
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	0.49	N
REVEL	Benign	0.17
Sift	Benign	0.35	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.29		Loss of helix (P = 0.0033)
MVP		0.42
ClinPred		0.082	T
GERP RS		-2.1
Varity_R		0.12
gMVP		0.42
Mutation Taster		=83/17	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-139586166;