chrX-140503952-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_005634.3(SOX3):ā€‹c.1109T>Cā€‹(p.Met370Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,150,493 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. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000028 ( 0 hom., 0 hem., cov: 23)
Exomes š‘“: 0.000016 ( 0 hom. 2 hem. )

Consequence

SOX3
NM_005634.3 missense

Scores

2
4
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.58
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.27839577).
BS2
High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SOX3NM_005634.3 linkuse as main transcriptc.1109T>C p.Met370Thr missense_variant 1/1 ENST00000370536.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SOX3ENST00000370536.5 linkuse as main transcriptc.1109T>C p.Met370Thr missense_variant 1/1 NM_005634.3 P1

Frequencies

GnomAD3 genomes
AF:
0.0000277
AC:
3
AN:
108430
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
31822
show subpopulations
Gnomad AFR
AF:
0.0000669
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:
0.0000193
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000184
AC:
2
AN:
108937
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
30839
show subpopulations
Gnomad AFR exome
AF:
0.000378
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000163
AC:
17
AN:
1042063
Hom.:
0
Cov.:
31
AF XY:
0.00000605
AC XY:
2
AN XY:
330347
show subpopulations
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:
0.0000183
Gnomad4 OTH exome
AF:
0.0000227
GnomAD4 genome
AF:
0.0000277
AC:
3
AN:
108430
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
31822
show subpopulations
Gnomad4 AFR
AF:
0.0000669
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:
0.0000193
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
1
Bravo
AF:
0.0000302
ExAC
AF:
0.0000365
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJun 10, 2022This variant has not been reported in the literature in individuals affected with SOX3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 370 of the SOX3 protein (p.Met370Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Uncertain
0.056
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
21
DANN
Benign
0.89
DEOGEN2
Benign
0.39
T
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.79
D
MetaRNN
Benign
0.28
T
MetaSVM
Benign
-0.61
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.97
D
PROVEAN
Benign
-1.3
N
REVEL
Uncertain
0.42
Sift
Benign
0.061
T
Sift4G
Benign
0.99
T
Polyphen
0.17
B
Vest4
0.51
MutPred
0.17
Gain of glycosylation at M370 (P = 8e-04);
MVP
0.71
ClinPred
0.071
T
GERP RS
4.2
Varity_R
0.54
gMVP
0.38

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs756686652; hg19: chrX-139586117; API