16-30086236-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.1300C>T(p.Pro434Ser) 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 1,459,592 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. P434R) 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, single submitter U:1
• Conservation: PhyloP100: 3.57

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=0.18835783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX6	NM_004608.4	c.1300C>T	p.Pro434Ser	missense_variant	9/9	ENST00000395224.7
TBX6	XM_011545926.4	c.1300C>T	p.Pro434Ser	missense_variant	9/9
TBX6	XM_047434551.1	c.1300C>T	p.Pro434Ser	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX6	ENST00000395224.7	c.1300C>T	p.Pro434Ser	missense_variant	9/9	1	NM_004608.4	P1
TBX6	ENST00000279386.6	c.1300C>T	p.Pro434Ser	missense_variant	8/8	1		P1
TBX6	ENST00000567664.5	c.*434C>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459592 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726144

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Scoliosis Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

Aug 01, 2019

This variant may contribute to congenital scoliosis development -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Uncertain	-0.041	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	0.60	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N;N;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.099	B;B;.
Vest4		0.16
MutPred		0.32		Gain of phosphorylation at P434 (P = 0.0388);Gain of phosphorylation at P434 (P = 0.0388);Gain of phosphorylation at P434 (P = 0.0388);
MVP		0.82
MPC		0.21
ClinPred		0.79	D
GERP RS		4.7
Varity_R		0.097
gMVP		0.38

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: rs1200121314; hg19: chr16-30097557;