13-27792898-C-A

Position:

• chr13-27792898-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145657.3(GSX1):​c.208C>A​(p.Pro70Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,372,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000015 (0 hom.)
• Consequence: GSX1 NM_145657.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3752814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSX1	NM_145657.3	c.208C>A	p.Pro70Thr	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.208C>A	p.Pro70Thr	missense_variant	1/2	1	NM_145657.3	ENSP00000304331.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1372270 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 676924

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000287

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: 9.32e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

May 13, 2024

The c.208C>A (p.P70T) 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 208, causing the proline (P) at amino acid position 70 to be replaced by a threonine (T). 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	0.068
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.068
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.074	D
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.27	N
REVEL	Uncertain	0.38
Sift	Benign	0.034	D
Sift4G	Benign	0.24	T
Polyphen		0.86	P
Vest4		0.32
MutPred		0.41		Gain of catalytic residue at S65 (P = 0);
MVP		0.91
MPC		0.86
ClinPred		0.61	D
GERP RS		4.1
Varity_R		0.18
gMVP		0.52

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: rs567910687; hg19: chr13-28367035;