Genetic Variant GBX1:p.Ala125Thr (chr7-151167176-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001098834.3(GBX1):c.373G>A(p.Ala125Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,574,880 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

GBX1
NM_001098834.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.122

Variant links:

Genes affected

GBX1 (HGNC:4185): (gastrulation brain homeobox 1) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of nervous system development and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within adult walking behavior; neuron differentiation; and proprioception. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

GBX1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19818127).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBX1	NM_001098834.3 link	c.373G>A	p.Ala125Thr	missense_variant	Exon 1 of 2	ENST00000297537.5	NP_001092304.1	Q14549

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBX1	ENST00000297537.5 link	c.373G>A	p.Ala125Thr	missense_variant	Exon 1 of 2	1	NM_001098834.3	ENSP00000297537.4		Q14549
GBX1	ENST00000475831.1 link	n.146G>A		non_coding_transcript_exon_variant	Exon 2 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.0000661

AC:

AN:

151208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000170

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00327

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000323

AC:

AN:

185812

Hom.:

AF XY:

0.0000483

AC XY:

AN XY:

103586

show subpopulations

Gnomad AFR exome

AF:

0.000117

Gnomad AMR exome

AF:

0.0000362

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000762

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000254

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000155

AC:

AN:

1423568

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

706226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000644

Gnomad4 AMR exome

AF:

0.0000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000363

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000548

Gnomad4 OTH exome

AF:

0.000119

GnomAD4 genome

AF:

0.0000595

AC:

AN:

151312

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

73938

show subpopulations

Gnomad4 AFR

AF:

0.000170

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000375

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.373G>A (p.A125T) alteration is located in exon 1 (coding exon 1) of the GBX1 gene. This alteration results from a G to A substitution at nucleotide position 373, causing the alanine (A) at amino acid position 125 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

0.10

BayesDel_addAF

Benign

0.0095

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.23

REVEL

Benign

0.17

Sift

Uncertain

0.020

Sift4G

Benign

0.11

Polyphen

0.027

Vest4

0.21

MutPred

0.41

Gain of glycosylation at A125 (P = 0.0042);

MVP

0.79

MPC

0.73

ClinPred

0.075

GERP RS

0.67

Varity_R

0.10

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over