4-54100558-T-A

Variant names:

• chr4-54100558-T-A
• rs768017023
• NM_133267.3:c.214T>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.214T>A​(p.Ser72Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000812 in 1,600,212 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. 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. S72P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: GSX2 NM_133267.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.721
• Publications: 2 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=0.14387313).

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.214T>A	p.Ser72Thr	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.214T>A	p.Ser72Thr	missense	Exon 1 of 2	ENSP00000319118.2	Q9BZM3
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1018-174367T>A		intron	N/A	ENSP00000423325.1	A0A0B4J203
	GSX2	ENST00000503800.1	TSL:5	c.214T>A	p.Ser72Thr	missense	Exon 1 of 2	ENSP00000422213.1	D6R903

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151608 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000228 AC: 5 AN: 219462 AF XY: 0.0000332

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000240

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000828 AC: 12 AN: 1448490 Hom.: 0 Cov.: 64 AF XY: 0.0000111 AC XY: 8 AN XY: 719710

African (AFR) AF: 0.00 AC: 0 AN: 33216

American (AMR) AF: 0.00 AC: 0 AN: 43330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25710

East Asian (EAS) AF: 0.000128 AC: 5 AN: 39106

South Asian (SAS) AF: 0.0000356 AC: 3 AN: 84174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107224

Other (OTH) AF: 0.0000334 AC: 2 AN: 59874

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151722 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74178

African (AFR) AF: 0.00 AC: 0 AN: 41316

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67910

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000416 AC: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.72
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.11
Sift	Uncertain	0.017	D
Sift4G	Benign	0.74	T
Polyphen		0.034	B
Vest4		0.26
MutPred		0.28		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.90
MPC		0.74
ClinPred		0.041	T
GERP RS		1.9
PromoterAI		-0.017	Neutral
Varity_R		0.14
gMVP		0.26
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs768017023; hg19: chr4-54966725;