16-30086309-C-T

Variant names:

• chr16-30086309-C-T
• rs2289292
• NM_004608.4:c.1227G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004608.4(TBX6):​c.1227G>A​(p.Pro409Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 1,610,118 control chromosomes in the GnomAD database, including 90,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P409P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (6811 hom., cov: 32)
  • Exomes 𝑓: 0.33 (83970 hom.)
• Consequence: TBX6 NM_004608.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.57
• Publications: 51 publications found

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]

TBX6 Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 5

  Inheritance: Unknown, SD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant spondylocostal dysostosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital anomaly of kidney and urinary tract

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 16-30086309-C-T is Benign according to our data. Variant chr16-30086309-C-T is described in CliVar as Benign. Clinvar id is 259448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30086309-C-T is described in CliVar as Benign. Clinvar id is 259448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30086309-C-T is described in CliVar as Benign. Clinvar id is 259448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30086309-C-T is described in CliVar as Benign. Clinvar id is 259448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30086309-C-T is described in CliVar as Benign. Clinvar id is 259448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30086309-C-T is described in CliVar as Benign. Clinvar id is 259448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30086309-C-T is described in CliVar as Benign. Clinvar id is 259448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX6	NM_004608.4	c.1227G>A	p.Pro409Pro	synonymous_variant	Exon 9 of 9	ENST00000395224.7	NP_004599.2
TBX6	XM_011545926.4	c.1227G>A	p.Pro409Pro	synonymous_variant	Exon 9 of 9		XP_011544228.1
TBX6	XM_047434551.1	c.1227G>A	p.Pro409Pro	synonymous_variant	Exon 8 of 8		XP_047290507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX6	ENST00000395224.7	c.1227G>A	p.Pro409Pro	synonymous_variant	Exon 9 of 9	1	NM_004608.4	ENSP00000378650.2
TBX6	ENST00000279386.6	c.1227G>A	p.Pro409Pro	synonymous_variant	Exon 8 of 8	1		ENSP00000279386.2
TBX6	ENST00000567664.5	n.*361G>A		non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000460425.1
TBX6	ENST00000567664.5	n.*361G>A		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000460425.1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40659 AN: 151964 Hom.: 6809 Cov.: 32

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.283

GnomAD2 exomes AF: 0.326 AC: 79650 AN: 244618 AF XY: 0.324

Gnomad AFR exome AF: 0.0610

Gnomad AMR exome AF: 0.340

Gnomad ASJ exome AF: 0.312

Gnomad EAS exome AF: 0.456

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.347

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.333 AC: 485194 AN: 1458036 Hom.: 83970 Cov.: 54 AF XY: 0.330 AC XY: 239636 AN XY: 725400

African (AFR) AF: 0.0592 AC: 1973 AN: 33328

American (AMR) AF: 0.340 AC: 14906 AN: 43838

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 7959 AN: 25938

East Asian (EAS) AF: 0.535 AC: 21178 AN: 39612

South Asian (SAS) AF: 0.231 AC: 19913 AN: 86070

European-Finnish (FIN) AF: 0.426 AC: 22698 AN: 53308

Middle Eastern (MID) AF: 0.266 AC: 1310 AN: 4918

European-Non Finnish (NFE) AF: 0.339 AC: 376207 AN: 1110896

Other (OTH) AF: 0.317 AC: 19050 AN: 60128

GnomAD4 genome AF: 0.267 AC: 40667 AN: 152082 Hom.: 6811 Cov.: 32 AF XY: 0.271 AC XY: 20158 AN XY: 74332

African (AFR) AF: 0.0694 AC: 2883 AN: 41524

American (AMR) AF: 0.298 AC: 4557 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1100 AN: 3472

East Asian (EAS) AF: 0.468 AC: 2412 AN: 5150

South Asian (SAS) AF: 0.233 AC: 1123 AN: 4824

European-Finnish (FIN) AF: 0.420 AC: 4440 AN: 10582

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.341 AC: 23131 AN: 67930

Other (OTH) AF: 0.286 AC: 605 AN: 2112

Alfa AF: 0.282 Hom.: 3062

Bravo AF: 0.257

Asia WGS AF: 0.354 AC: 1229 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 28, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.45
DANN	Benign	0.89
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2289292; hg19: chr16-30097630; COSMIC: COSV54221665; COSMIC: COSV54221665;