4-54100714-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133267.3(GSX2):​c.370C>A​(p.His124Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,396,636 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: GSX2 NM_133267.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.882

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]

ENSG00000282278 (HGNC:):

ACMG classification

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=0.20917806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSX2	NM_133267.3	c.370C>A	p.His124Asn	missense_variant	Exon 1 of 2	ENST00000326902.7	NP_573574.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSX2	ENST00000326902.7	c.370C>A	p.His124Asn	missense_variant	Exon 1 of 2	1	NM_133267.3	ENSP00000319118.2
ENSG00000282278	ENST00000507166.5	c.1018-174211C>A		intron_variant	Intron 12 of 23	2		ENSP00000423325.1
GSX2	ENST00000503800.1	c.363+7C>A		splice_region_variant, intron_variant	Intron 1 of 1	5		ENSP00000422213.1
GSX2	ENST00000507839.1	n.115-868C>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1396636 Hom.: 0 Cov.: 47 AF XY: 0.00000290 AC XY: 2 AN XY: 688888

Gnomad4 AFR exome AF: 0.0000319

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: 9.27e-7

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000451 Hom.: 0

ExAC AF: 0.0000299 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.370C>A (p.H124N) 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 370, causing the histidine (H) at amino acid position 124 to be replaced by an asparagine (N). 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	0.091
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.53	T;.
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.46	.;N
REVEL	Benign	0.25
Sift	Uncertain	0.014	.;D
Sift4G	Benign	0.11	T;T
Polyphen		0.0	B;B
Vest4		0.28
MutPred		0.32		Loss of catalytic residue at H124 (P = 0.0749);Loss of catalytic residue at H124 (P = 0.0749);
MVP		0.91
MPC		1.9
ClinPred		0.43	T
GERP RS		3.3
Varity_R		0.21
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs758503759; hg19: chr4-54966881;