4-54100688-A-G

Variant names:

• chr4-54100688-A-G
• rs1397964236
• NM_133267.3:c.344A>G

Variant summary

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

The NM_133267.3(GSX2):​c.344A>G​(p.Asp115Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSX2 NM_133267.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

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=0.19228297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSX2	NM_133267.3	c.344A>G	p.Asp115Gly	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.344A>G	p.Asp115Gly	missense_variant	Exon 1 of 2	1	NM_133267.3	ENSP00000319118.2
ENSG00000282278	ENST00000507166.5	c.1018-174237A>G		intron_variant	Intron 12 of 23	2		ENSP00000423325.1
GSX2	ENST00000503800.1	c.344A>G	p.Asp115Gly	missense_variant	Exon 1 of 2	5		ENSP00000422213.1
GSX2	ENST00000507839.1	n.115-894A>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1396848 Hom.: 0 Cov.: 47 AF XY: 0.00 AC XY: 0 AN XY: 688992

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.344A>G (p.D115G) alteration is located in exon 1 (coding exon 1) of the GSX2 gene. This alteration results from a A to G substitution at nucleotide position 344, causing the aspartic acid (D) at amino acid position 115 to be replaced by a glycine (G). 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	0.13
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.10	T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.72	T;.;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.44	N;N;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.28	.;N;N
REVEL	Benign	0.25
Sift	Benign	0.41	.;T;D
Sift4G	Benign	0.49	T;T;T
Polyphen		0.21	B;B;.
Vest4		0.15
MutPred		0.23		Loss of glycosylation at S111 (P = 0.0297);Loss of glycosylation at S111 (P = 0.0297);Loss of glycosylation at S111 (P = 0.0297);
MVP		0.84
MPC		1.4
ClinPred		0.21	T
GERP RS		2.8
Varity_R		0.12
gMVP		0.44

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: rs1397964236; hg19: chr4-54966855;