16-30086235-G-C

Variant summary

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

The NM_004608.4(TBX6):c.1301C>G(p.Pro434Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P434S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX6 NM_004608.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49

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=0.1657007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX6	NM_004608.4	c.1301C>G	p.Pro434Arg	missense_variant	9/9	ENST00000395224.7
TBX6	XM_011545926.4	c.1301C>G	p.Pro434Arg	missense_variant	9/9
TBX6	XM_047434551.1	c.1301C>G	p.Pro434Arg	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX6	ENST00000395224.7	c.1301C>G	p.Pro434Arg	missense_variant	9/9	1	NM_004608.4	P1
TBX6	ENST00000279386.6	c.1301C>G	p.Pro434Arg	missense_variant	8/8	1		P1
TBX6	ENST00000567664.5	c.*435C>G		3_prime_UTR_variant, NMD_transcript_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

GeneDx

Jun 29, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	19
Dann	Benign	0.94
DEOGEN2	Uncertain	0.51	D;D;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.69	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	0.83	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.1	D;D;.
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.099	B;B;.
Vest4		0.36
MutPred		0.36		Gain of MoRF binding (P = 0.0233);Gain of MoRF binding (P = 0.0233);Gain of MoRF binding (P = 0.0233);
MVP		0.71
MPC		0.26
ClinPred		0.48	T
GERP RS		2.7
Varity_R		0.18
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-30097556;