16-30086309-C-T

Variant names:

• chr16-30086309-C-T
• rs2289292
• NM_004608.4:c.1227G>A
• TBX6 p.Pro409Pro

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P409P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.27 (6811 hom., cov: 32)
  • Exomes 𝑓: 0.33 (83970 hom.)
• Consequence: TBX6 NM_004608.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -2.57
• Publications: 53 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):

• Mayer-Rokitansky-Kuster-Hauser syndrome

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• spondylocostal dysostosis 5

  Inheritance: AR, Unknown, SD Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, 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 -14 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 ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259448.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004608.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX6	NM_004608.4	MANE Select	c.1227G>A	p.Pro409Pro	synonymous	Exon 9 of 9	NP_004599.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX6	ENST00000395224.7	TSL:1 MANE Select	c.1227G>A	p.Pro409Pro	synonymous	Exon 9 of 9	ENSP00000378650.2	O95947-1
	TBX6	ENST00000279386.6	TSL:1	c.1227G>A	p.Pro409Pro	synonymous	Exon 8 of 8	ENSP00000279386.2	O95947-1
	TBX6	ENST00000931584.1		c.1323G>A	p.Pro441Pro	synonymous	Exon 8 of 8	ENSP00000601643.1

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2289292;

hg19: chr16-30097630;

COSMIC: COSV54221665;

COSMIC: COSV54221665;