16-30086232-A-G

Position:

• chr16-30086232-A-G

Variant summary

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

The NM_004608.4(TBX6):​c.1304T>C​(p.Met435Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,346 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBX6 NM_004608.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.33

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=0.27221155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX6	NM_004608.4	c.1304T>C	p.Met435Thr	missense_variant	9/9	ENST00000395224.7	NP_004599.2
TBX6	XM_011545926.4	c.1304T>C	p.Met435Thr	missense_variant	9/9		XP_011544228.1
TBX6	XM_047434551.1	c.1304T>C	p.Met435Thr	missense_variant	8/8		XP_047290507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX6	ENST00000395224.7	c.1304T>C	p.Met435Thr	missense_variant	9/9	1	NM_004608.4	ENSP00000378650.2
TBX6	ENST00000279386.6	c.1304T>C	p.Met435Thr	missense_variant	8/8	1		ENSP00000279386.2
TBX6	ENST00000567664.5	n.*438T>C		non_coding_transcript_exon_variant	7/7	5		ENSP00000460425.1
TBX6	ENST00000567664.5	n.*438T>C		3_prime_UTR_variant	7/7	5		ENSP00000460425.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459346 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726006

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: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Benign	0.79
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.64	.;T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.44	N;N;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.028	D;D;D
Polyphen		0.0	B;B;.
Vest4		0.41
MutPred		0.25		Gain of glycosylation at M435 (P = 0.007);Gain of glycosylation at M435 (P = 0.007);Gain of glycosylation at M435 (P = 0.007);
MVP		0.88
MPC		0.23
ClinPred		0.30	T
GERP RS		4.7
Varity_R		0.69
gMVP		0.45

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: rs2072625047; hg19: chr16-30097553;