X-140504934-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005634.3(SOX3):​c.127G>A​(p.Ala43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,198,480 control chromosomes in the GnomAD database, including 155 homozygotes. There are 1,328 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (74 hom., 655 hem., cov: 24)
  • Exomes 𝑓: 0.0025 (81 hom. 673 hem.)
• Consequence: SOX3 NM_005634.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015605986).
• BP6: Variant X-140504934-C-T is Benign according to our data. Variant chrX-140504934-C-T is described in ClinVar as Benign. ClinVar VariationId is 193322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0747 is higher than 0.05.

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.127G>A	p.Ala43Thr	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.127G>A	p.Ala43Thr	missense	Exon 1 of 1	ENSP00000359567.2
	ENSG00000303910	ENST00000797999.1		n.105+1086C>T		intron	N/A
	ENSG00000303910	ENST00000798000.1		n.158+1310C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 2546 AN: 112841 Hom.: 74 Cov.: 24

Gnomad AFR AF: 0.0773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00940

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000366

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000131

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.00628 AC: 939 AN: 149416 AF XY: 0.00372

Gnomad AFR exome AF: 0.0859

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00437

GnomAD4 exome AF: 0.00250 AC: 2711 AN: 1085592 Hom.: 81 Cov.: 33 AF XY: 0.00189 AC XY: 673 AN XY: 355352

African (AFR) AF: 0.0848 AC: 2197 AN: 25893

American (AMR) AF: 0.00446 AC: 152 AN: 34081

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 29032

South Asian (SAS) AF: 0.000153 AC: 8 AN: 52247

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

Middle Eastern (MID) AF: 0.00198 AC: 8 AN: 4034

European-Non Finnish (NFE) AF: 0.000114 AC: 95 AN: 836424

Other (OTH) AF: 0.00551 AC: 251 AN: 45569

GnomAD4 genome AF: 0.0226 AC: 2548 AN: 112888 Hom.: 74 Cov.: 24 AF XY: 0.0187 AC XY: 655 AN XY: 35066

African (AFR) AF: 0.0772 AC: 2401 AN: 31091

American (AMR) AF: 0.00939 AC: 102 AN: 10867

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.000367 AC: 1 AN: 2723

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000131 AC: 7 AN: 53291

Other (OTH) AF: 0.0242 AC: 37 AN: 1532

Alfa AF: 0.00712 Hom.: 261

Bravo AF: 0.0259

ESP6500AA AF: 0.0695 AC: 265

ESP6500EA AF: 0.000449 AC: 3

ExAC AF: 0.00656 AC: 788

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.8
DANN	Benign	0.94
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.58
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.14	N
REVEL	Uncertain	0.29
Sift	Benign	0.31	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.0040
MVP		0.27
ClinPred		0.0027	T
GERP RS		0.84
PromoterAI		-0.019	Neutral
Varity_R		0.044
gMVP		0.14
Mutation Taster		=99/1	polymorphism (auto)

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;