7-151167311-C-T

Variant names:

• chr7-151167311-C-T
• rs1801269454
• NM_001098834.3:c.238G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001098834.3(GBX1):​c.238G>A​(p.Ala80Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,371,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A80P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: GBX1 NM_001098834.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13675165).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098834.3. 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
	GBX1	NM_001098834.3	MANE Select	c.238G>A	p.Ala80Thr	missense	Exon 1 of 2	NP_001092304.1	Q14549

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBX1	ENST00000297537.5	TSL:1 MANE Select	c.238G>A	p.Ala80Thr	missense	Exon 1 of 2	ENSP00000297537.4	Q14549
	GBX1	ENST00000475831.1	TSL:4	n.131-120G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1371026 Hom.: 0 Cov.: 33 AF XY: 0.00000296 AC XY: 2 AN XY: 676474

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28042

American (AMR) AF: 0.00 AC: 0 AN: 31700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23586

East Asian (EAS) AF: 0.00 AC: 0 AN: 32322

South Asian (SAS) AF: 0.00 AC: 0 AN: 75504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5458

European-Non Finnish (NFE) AF: 0.00000280 AC: 3 AN: 1070368

Other (OTH) AF: 0.00 AC: 0 AN: 56666

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.2
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.042
Sift	Benign	0.20	T
Sift4G	Benign	0.41	T
Polyphen		0.25	B
Vest4		0.27
MutPred		0.54		Gain of phosphorylation at A80 (P = 0.0502)
MVP		0.48
MPC		1.3
ClinPred		0.84	D
GERP RS		2.8
PromoterAI		-0.022	Neutral
Varity_R		0.10
gMVP		0.58
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs1801269454; hg19: chr7-150864398;