X-140504055-T-A

Position:

• chrX-140504055-T-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_005634.3(SOX3):​c.1006A>T​(p.Met336Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 861,525 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000058 (0 hom. 3 hem.)
• Consequence: SOX3 NM_005634.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.65

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19998533).
• BP6: Variant X-140504055-T-A is Benign according to our data. Variant chrX-140504055-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 3389129.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX3	NM_005634.3	c.1006A>T	p.Met336Leu	missense_variant	1/1	ENST00000370536.5	NP_005625.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX3	ENST00000370536.5	c.1006A>T	p.Met336Leu	missense_variant	1/1	6	NM_005634.3	ENSP00000359567.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000580 AC: 5 AN: 861525 Hom.: 0 Cov.: 27 AF XY: 0.0000114 AC XY: 3 AN XY: 263793

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000690

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

SOX3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.52
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.55	N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.27
Sift	Benign	0.19	T
Sift4G	Benign	0.66	T
Polyphen		0.16	B
Vest4		0.29
MutPred		0.27		Loss of loop (P = 0.0288);
MVP		0.48
ClinPred		0.18	T
GERP RS		3.6
Varity_R		0.31
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs1387584167; hg19: chrX-139586220;