16-30086293-C-G

Variant summary

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

The NM_004608.4(TBX6):c.1243G>C(p.Gly415Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G415V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TBX6 NM_004608.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0160

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31006896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX6	NM_004608.4	c.1243G>C	p.Gly415Arg	missense_variant	9/9	ENST00000395224.7
TBX6	XM_011545926.4	c.1243G>C	p.Gly415Arg	missense_variant	9/9
TBX6	XM_047434551.1	c.1243G>C	p.Gly415Arg	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX6	ENST00000395224.7	c.1243G>C	p.Gly415Arg	missense_variant	9/9	1	NM_004608.4	P1
TBX6	ENST00000279386.6	c.1243G>C	p.Gly415Arg	missense_variant	8/8	1		P1
TBX6	ENST00000567664.5	c.*377G>C		3_prime_UTR_variant, NMD_transcript_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459464 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726032

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: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.1243G>C (p.G415R) alteration is located in exon 9 (coding exon 8) of the TBX6 gene. This alteration results from a G to C substitution at nucleotide position 1243, causing the glycine (G) at amino acid position 415 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

TBX6: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.63	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	0.91	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;D;.
Sift4G	Benign	0.077	T;T;D
Polyphen		0.62	P;P;.
Vest4		0.43
MutPred		0.43		Gain of methylation at G415 (P = 0.0285);Gain of methylation at G415 (P = 0.0285);Gain of methylation at G415 (P = 0.0285);
MVP		0.87
MPC		0.42
ClinPred		0.39	T
GERP RS		3.8
Varity_R		0.17
gMVP		0.44

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: rs1177425852; hg19: chr16-30097614;