NM_133267.3:c.358C>A

Variant names:

• chr4-54100702-C-A
• rs796644145
• NM_133267.3:c.358C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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. 14/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16046727).

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.358C>A	p.Pro120Thr	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.358C>A	p.Pro120Thr	missense	Exon 1 of 2	ENSP00000319118.2	Q9BZM3
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1018-174223C>A		intron	N/A	ENSP00000423325.1	A0A0B4J203
	GSX2	ENST00000503800.1	TSL:5	c.358C>A	p.Pro120Thr	missense	Exon 1 of 2	ENSP00000422213.1	D6R903

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152128 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: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000203 AC: 3 AN: 148146 AF XY: 0.0000253

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000234

GnomAD4 exome AF: 0.00000787 AC: 11 AN: 1397066 Hom.: 0 Cov.: 47 AF XY: 0.00000871 AC XY: 6 AN XY: 689084

African (AFR) AF: 0.00 AC: 0 AN: 31436

American (AMR) AF: 0.00 AC: 0 AN: 35616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25094

East Asian (EAS) AF: 0.00 AC: 0 AN: 35600

South Asian (SAS) AF: 0.000114 AC: 9 AN: 79192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078380

Other (OTH) AF: 0.0000345 AC: 2 AN: 57910

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74410

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.081
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.43		Gain of helix (P = 0.0325)
MVP		0.83
MPC		0.89
ClinPred		0.10	T
GERP RS		-0.11
Varity_R		0.15
gMVP		0.43
Mutation Taster		=93/7	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: rs796644145; hg19: chr4-54966869;