chr7-151167493-C-T

Position:

• chr7-151167493-C-T

Variant summary

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

The NM_001098834.3(GBX1):​c.56G>A​(p.Gly19Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000749 in 1,335,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: GBX1 NM_001098834.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53

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]

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
GBX1	NM_001098834.3	c.56G>A	p.Gly19Glu	missense_variant	1/2	ENST00000297537.5	NP_001092304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBX1	ENST00000297537.5	c.56G>A	p.Gly19Glu	missense_variant	1/2	1	NM_001098834.3	ENSP00000297537.4
GBX1	ENST00000475831.1	n.131-302G>A		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.49e-7 AC: 1 AN: 1335220 Hom.: 0 Cov.: 33 AF XY: 0.00000152 AC XY: 1 AN XY: 658738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000429

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Aug 25, 2024

The c.56G>A (p.G19E) 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 56, causing the glycine (G) at amino acid position 19 to be replaced by a glutamic acid (E). 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	0.21
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-0.067
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.5	L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.080	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.017	D
Polyphen		0.96	D
Vest4		0.30
MutPred		0.17		Gain of solvent accessibility (P = 0.0456);
MVP		0.89
MPC		0.96
ClinPred		0.57	D
GERP RS		2.0
Varity_R		0.098
gMVP		0.24

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: rs1476295035; hg19: chr7-150864580;