13-27792892-C-A

Position:

• chr13-27792892-C-A

Variant summary

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

The NM_145657.3(GSX1):​c.202C>A​(p.His68Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000401 in 1,372,932 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: GSX1 NM_145657.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.05

Genes affected

GSX1 (HGNC:20374): (GS homeobox 1) Enables sequence-specific double-stranded DNA binding activity. Acts upstream of or within positive regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSX1	NM_145657.3	c.202C>A	p.His68Asn	missense_variant	1/2	ENST00000302945.3	NP_663632.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSX1	ENST00000302945.3	c.202C>A	p.His68Asn	missense_variant	1/2	1	NM_145657.3	ENSP00000304331.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000401 AC: 55 AN: 1372932 Hom.: 0 Cov.: 30 AF XY: 0.0000458 AC XY: 31 AN XY: 677252

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: 0.0000512

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.202C>A (p.H68N) alteration is located in exon 1 (coding exon 1) of the GSX1 gene. This alteration results from a C to A substitution at nucleotide position 202, causing the histidine (H) at amino acid position 68 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	0.18
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.16	T
Polyphen		0.90	P
Vest4		0.51
MutPred		0.34		Gain of catalytic residue at S65 (P = 0);
MVP		0.96
MPC		1.1
ClinPred		0.49	T
GERP RS		4.1
Varity_R		0.54
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs745373226; hg19: chr13-28367029;