NM_133267.3:c.370C>G

Variant names:

• chr4-54100714-C-G
• rs758503759
• NM_133267.3:c.370C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_133267.3(GSX2):​c.370C>G​(p.His124Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000194 in 1,548,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H124N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GSX2 NM_133267.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.882
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• diencephalic-mesencephalic junction dysplasia syndrome 2

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000282278 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2910695).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133267.3. 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
	GSX2	NM_133267.3	MANE Select	c.370C>G	p.His124Asp	missense	Exon 1 of 2	NP_573574.2	Q9BZM3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSX2	ENST00000326902.7	TSL:1 MANE Select	c.370C>G	p.His124Asp	missense	Exon 1 of 2	ENSP00000319118.2	Q9BZM3
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1018-174211C>G		intron	N/A	ENSP00000423325.1	A0A0B4J203
	GSX2	ENST00000503800.1	TSL:5	c.363+7C>G		splice_region intron	N/A	ENSP00000422213.1	D6R903

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000204 AC: 3 AN: 146834 AF XY: 0.0000127

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000816

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000235

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1396636 Hom.: 0 Cov.: 47 AF XY: 0.00000145 AC XY: 1 AN XY: 688888

African (AFR) AF: 0.00 AC: 0 AN: 31378

American (AMR) AF: 0.0000562 AC: 2 AN: 35610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25076

East Asian (EAS) AF: 0.00 AC: 0 AN: 35538

South Asian (SAS) AF: 0.00 AC: 0 AN: 79176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078188

Other (OTH) AF: 0.00 AC: 0 AN: 57894

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74288

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.88
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.013	D
Sift4G	Benign	0.073	T
Polyphen		0.063	B
Vest4		0.37
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.82
MPC		2.1
ClinPred		0.62	D
GERP RS		3.3
Varity_R		0.27
gMVP		0.33
Mutation Taster		=70/30	polymorphism

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: rs758503759; hg19: chr4-54966881;