chr4-54100663-G-A

Variant names:

• chr4-54100663-G-A
• rs13144341
• NM_133267.3:c.319G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133267.3(GSX2):​c.319G>A​(p.Gly107Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 152,192 control chromosomes in the GnomAD database, including 75,365 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75365 hom., cov: 31)
  • Exomes 𝑓: 1.0 (697774 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSX2 NM_133267.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0180
• Publications: 17 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.4659404E-7).
• BP6: Variant 4-54100663-G-A is Benign according to our data. Variant chr4-54100663-G-A is described in ClinVar as Benign. ClinVar VariationId is 1285310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

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.319G>A	p.Gly107Ser	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.319G>A	p.Gly107Ser	missense	Exon 1 of 2	ENSP00000319118.2	Q9BZM3
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1018-174262G>A		intron	N/A	ENSP00000423325.1	A0A0B4J203
	GSX2	ENST00000503800.1	TSL:5	c.319G>A	p.Gly107Ser	missense	Exon 1 of 2	ENSP00000422213.1	D6R903

Frequencies

GnomAD3 genomes AF: 0.995 AC: 151338 AN: 152074 Hom.: 75307 Cov.: 31

Gnomad AFR AF: 0.983

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.997

GnomAD2 exomes AF: 0.999 AC: 148852 AN: 149028 AF XY: 0.999

Gnomad AFR exome AF: 0.982

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.999 AC: 1396288 AN: 1397032 Hom.: 697774 Cov.: 64 AF XY: 1.00 AC XY: 688825 AN XY: 689134

African (AFR) AF: 0.980 AC: 30834 AN: 31478

American (AMR) AF: 0.999 AC: 35249 AN: 35282

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25110 AN: 25110

East Asian (EAS) AF: 1.00 AC: 35712 AN: 35712

South Asian (SAS) AF: 1.00 AC: 79185 AN: 79188

European-Finnish (FIN) AF: 1.00 AC: 48358 AN: 48358

Middle Eastern (MID) AF: 0.999 AC: 5604 AN: 5610

European-Non Finnish (NFE) AF: 1.00 AC: 1078408 AN: 1078418

Other (OTH) AF: 0.999 AC: 57828 AN: 57876

GnomAD4 genome AF: 0.995 AC: 151455 AN: 152192 Hom.: 75365 Cov.: 31 AF XY: 0.995 AC XY: 74054 AN XY: 74396

African (AFR) AF: 0.983 AC: 40843 AN: 41550

American (AMR) AF: 0.999 AC: 15284 AN: 15302

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3466 AN: 3466

East Asian (EAS) AF: 1.00 AC: 5134 AN: 5134

South Asian (SAS) AF: 1.00 AC: 4810 AN: 4810

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10620

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67988 AN: 67994

Other (OTH) AF: 0.997 AC: 2104 AN: 2110

Alfa AF: 0.999 Hom.: 125334

Bravo AF: 0.994

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.986 AC: 3893

ESP6500EA AF: 1.00 AC: 7589

ExAC AF: 0.997 AC: 63757

Asia WGS AF: 0.999 AC: 3470 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Diencephalic-mesencephalic junction dysplasia syndrome 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.077	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	5.5e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.23	N
PhyloP100		-0.018
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	0.41	N
REVEL	Benign	0.091
Sift	Benign	1.0	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.78
ClinPred		0.00061	T
GERP RS		1.4
PromoterAI		-0.0072	Neutral
Varity_R		0.038
gMVP		0.21
Mutation Taster		=95/5	polymorphism (auto)

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: rs13144341; hg19: chr4-54966830; COSMIC: COSV58843128; COSMIC: COSV58843128;