NM_005634.3:c.127G>C

Variant names:

• chrX-140504934-C-G
• rs73637709
• NM_005634.3:c.127G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005634.3(SOX3):​c.127G>C​(p.Ala43Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000368 in 1,085,595 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. A43T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000037 (0 hom. 2 hem.)
• Consequence: SOX3 NM_005634.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.579
• Publications: 10 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06827885).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX3	NM_005634.3	c.127G>C	p.Ala43Pro	missense_variant	Exon 1 of 1	ENST00000370536.5	NP_005625.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX3	ENST00000370536.5	c.127G>C	p.Ala43Pro	missense_variant	Exon 1 of 1	6	NM_005634.3	ENSP00000359567.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000669 AC: 1 AN: 149416 AF XY: 0.0000211

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000879

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000368 AC: 4 AN: 1085595 Hom.: 0 Cov.: 33 AF XY: 0.00000563 AC XY: 2 AN XY: 355355

African (AFR) AF: 0.00 AC: 0 AN: 25896

American (AMR) AF: 0.00 AC: 0 AN: 34081

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19162

East Asian (EAS) AF: 0.0000344 AC: 1 AN: 29032

South Asian (SAS) AF: 0.0000383 AC: 2 AN: 52247

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4034

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 836424

Other (OTH) AF: 0.00 AC: 0 AN: 45569

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.72
DANN	Benign	0.79
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.068	T
MetaSVM	Uncertain	0.0075	D
MutationAssessor	Benign	-0.34	N
PhyloP100		0.58
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.23
Sift	Benign	0.62	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.055
MutPred		0.20		Gain of glycosylation at A43 (P = 0.0062);
MVP		0.30
ClinPred		0.014	T
GERP RS		0.84
PromoterAI		-0.060	Neutral
Varity_R		0.078
gMVP		0.16
Mutation Taster		=100/0	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: rs73637709; hg19: chrX-139587099;