16-30086245-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004608.4(TBX6):c.1291G>A(p.Gly431Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,611,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: TBX6 NM_004608.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.791

Genes affected

TBX6 (HGNC:11605): (T-box transcription factor 6) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Knockout studies in mice indicate that this gene is important for specification of paraxial mesoderm structures. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1380476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX6	NM_004608.4	c.1291G>A	p.Gly431Ser	missense_variant	9/9	ENST00000395224.7
TBX6	XM_011545926.4	c.1291G>A	p.Gly431Ser	missense_variant	9/9
TBX6	XM_047434551.1	c.1291G>A	p.Gly431Ser	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX6	ENST00000395224.7	c.1291G>A	p.Gly431Ser	missense_variant	9/9	1	NM_004608.4	P1
TBX6	ENST00000279386.6	c.1291G>A	p.Gly431Ser	missense_variant	8/8	1		P1
TBX6	ENST00000567664.5	c.*425G>A		3_prime_UTR_variant, NMD_transcript_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000602 AC: 15 AN: 249162 Hom.: 0 AF XY: 0.0000741 AC XY: 10 AN XY: 134918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1459638 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 726174

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: 0.000169

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000996

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74296

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 30, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1509939). This variant has not been reported in the literature in individuals affected with TBX6-related conditions. This variant is present in population databases (rs772698551, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 431 of the TBX6 protein (p.Gly431Ser). -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 08, 2022	PP4, PM2_SUP, PM3, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.098	T;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.67	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	0.89	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.030	N;N;.
REVEL	Benign	0.23
Sift	Benign	0.12	T;T;.
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.22
MutPred		0.21		Gain of glycosylation at G431 (P = 0.0286);Gain of glycosylation at G431 (P = 0.0286);Gain of glycosylation at G431 (P = 0.0286);
MVP		0.77
MPC		0.21
ClinPred		0.052	T
GERP RS		3.7
Varity_R		0.061
gMVP		0.30

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: rs772698551; hg19: chr16-30097566;