16-30086310-G-A

Variant summary

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

The NM_004608.4(TBX6):c.1226C>T(p.Pro409Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,610,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P409P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: TBX6 NM_004608.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

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=0.14669153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX6	NM_004608.4	c.1226C>T	p.Pro409Leu	missense_variant	9/9	ENST00000395224.7
TBX6	XM_011545926.4	c.1226C>T	p.Pro409Leu	missense_variant	9/9
TBX6	XM_047434551.1	c.1226C>T	p.Pro409Leu	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX6	ENST00000395224.7	c.1226C>T	p.Pro409Leu	missense_variant	9/9	1	NM_004608.4	P1
TBX6	ENST00000279386.6	c.1226C>T	p.Pro409Leu	missense_variant	8/8	1		P1
TBX6	ENST00000567664.5	c.*360C>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000613 AC: 15 AN: 244846 Hom.: 0 AF XY: 0.0000375 AC XY: 5 AN XY: 133300

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: 0.000652

Gnomad NFE exome AF: 0.00000910

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 36 AN: 1458040 Hom.: 0 Cov.: 34 AF XY: 0.0000221 AC XY: 16 AN XY: 725444

Gnomad4 AFR exome AF: 0.0000300

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: 0.000525

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 409 of the TBX6 protein (p.Pro409Leu). This variant is present in population databases (rs747410580, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TBX6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1025432). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	0.93	D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.33	B;B;.
Vest4		0.22
MutPred		0.49		Loss of disorder (P = 0.0059);Loss of disorder (P = 0.0059);Loss of disorder (P = 0.0059);
MVP		0.94
MPC		0.21
ClinPred		0.13	T
GERP RS		3.3
Varity_R		0.063
gMVP		0.43

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: rs747410580; hg19: chr16-30097631; COSMIC: COSV54221298; COSMIC: COSV54221298;