4-54100370-C-A

Variant names:

• chr4-54100370-C-A
• rs1578004339
• NM_133267.3:c.26C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_133267.3(GSX2):​c.26C>A​(p.Ser9*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as no classifications from unflagged records (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GSX2 NM_133267.3 stop_gained
• Clinical Significance: no classifications from unflagged records no classifications from unflagged records P:1
• Conservation: PhyloP100: 7.52

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-54100370-C-A is Pathogenic according to our data. Variant chr4-54100370-C-A is described in ClinVar as [no_classifications_from_unflagged_records]. Clinvar id is 694062.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1}. Variant chr4-54100370-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSX2	NM_133267.3	c.26C>A	p.Ser9*	stop_gained	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.26C>A	p.Ser9*	stop_gained	Exon 1 of 2	1	NM_133267.3	ENSP00000319118.2
ENSG00000282278	ENST00000507166.5	c.1018-174555C>A		intron_variant	Intron 12 of 23	2		ENSP00000423325.1
GSX2	ENST00000503800.1	c.26C>A	p.Ser9*	stop_gained	Exon 1 of 2	5		ENSP00000422213.1
GSX2	ENST00000507839.1	n.114+734C>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

Submissions by phenotype

Diencephalic-mesencephalic junction dysplasia syndrome 2 Pathogenic:1

Aug 14, 2020

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.21
GERP RS		4.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1578004339; hg19: chr4-54966537; COSMIC: COSV58843244; COSMIC: COSV58843244;