X-140504053-C-T

Position:

• chrX-140504053-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005634.3(SOX3):​c.1008G>A​(p.Met336Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000351 in 969,953 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000037 (0 hom. 13 hem.)
• Consequence: SOX3 NM_005634.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.61

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25776428).
• BS2: High Hemizygotes in GnomAdExome4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX3	NM_005634.3	c.1008G>A	p.Met336Ile	missense_variant	1/1	ENST00000370536.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX3	ENST00000370536.5	c.1008G>A	p.Met336Ile	missense_variant	1/1		NM_005634.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000185 AC: 2 AN: 108393 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 31935

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000386

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000371 AC: 32 AN: 861560 Hom.: 0 Cov.: 27 AF XY: 0.0000493 AC XY: 13 AN XY: 263916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000876

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000372

Gnomad4 OTH exome AF: 0.0000851

GnomAD4 genome AF: 0.0000185 AC: 2 AN: 108393 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 31935

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000386

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000202 Hom.: 2

Bravo AF: 0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2021

The c.1008G>A (p.M336I) alteration is located in exon 1 (coding exon 1) of the SOX3 gene. This alteration results from a G to A substitution at nucleotide position 1008, causing the methionine (M) at amino acid position 336 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 16, 2023

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 336 of the SOX3 protein (p.Met336Ile). This variant is present in population databases (no rsID available, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with SOX3-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SOX3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.96	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.24
Sift	Benign	0.14	T
Sift4G	Benign	0.39	T
Polyphen		0.30	B
Vest4		0.37
MutPred		0.35		Loss of helix (P = 0.028);
MVP		0.45
ClinPred		0.25	T
GERP RS		3.6
Varity_R		0.41
gMVP		0.57

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: rs1319691356; hg19: chrX-139586218;