Genetic Variant GSX2:p.Pro120Thr (chr4-54100702-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_133267.3(GSX2):c.358C>A(p.Pro120Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000775 in 1,549,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

GSX2
NM_133267.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.26

Variant links:

Genes affected

GSX2 (HGNC:24959): (GS homeobox 2) Enables DNA-binding transcription factor activity, RNA polymerase II-specific and sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including nervous system development; positive regulation of Notch signaling pathway; and regulation of respiratory gaseous exchange by nervous system process. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

GSX2 links:

ENSG00000282278 (HGNC:):

ENSG00000282278 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16046727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSX2	NM_133267.3 link	c.358C>A	p.Pro120Thr	missense_variant	Exon 1 of 2	ENST00000326902.7	NP_573574.2	Q9BZM3B2LYG3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GSX2	ENST00000326902.7 link	c.358C>A	p.Pro120Thr	missense_variant	Exon 1 of 2	1	NM_133267.3	ENSP00000319118.2	Q9BZM3
ENSG00000282278	ENST00000507166.5 link	c.1018-174223C>A		intron_variant	Intron 12 of 23	2		ENSP00000423325.1	A0A0B4J203
GSX2	ENST00000503800.1 link	c.358C>A	p.Pro120Thr	missense_variant	Exon 1 of 2	5		ENSP00000422213.1	D6R903
GSX2	ENST00000507839.1 link	n.115-880C>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000203

AC:

AN:

148146

Hom.:

AF XY:

0.0000253

AC XY:

AN XY:

79182

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000882

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000234

GnomAD4 exome

AF:

0.00000787

AC:

AN:

1397066

Hom.:

Cov.:

AF XY:

0.00000871

AC XY:

AN XY:

689084

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:

0.000114

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.358C>A (p.P120T) alteration is located in exon 1 (coding exon 1) of the GSX2 gene. This alteration results from a C to A substitution at nucleotide position 358, causing the proline (P) at amino acid position 120 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.22

T;T;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.67

T;.;T

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.7

L;L;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.1

.;N;N

REVEL

Benign

0.081

Sift

Uncertain

0.0070

.;D;D

Sift4G

Benign

0.45

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.28

MutPred

0.43

Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);

MVP

0.83

MPC

0.89

ClinPred

0.10

GERP RS

-0.11

Varity_R

0.15

gMVP

0.43

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over