rs3809627

Variant names:

• chr16-30091839-C-A
• rs3809627
• ENST00000553607.1:c.-646G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-30091839-C-A
• chr16-30091839-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000553607.1(TBX6):​c.-646G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 152,336 control chromosomes in the GnomAD database, including 13,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.41 (13496 hom., cov: 33)
  • Exomes 𝑓: 0.35 (12 hom.)
• Consequence: TBX6 ENST00000553607.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.838
• Publications: 65 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: Unknown, AR, SD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-30091839-C-A is Benign according to our data. Variant chr16-30091839-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 427809.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000553607.1. 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.-49+34G>T		intron	N/A	NP_004599.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX6	ENST00000553607.1	TSL:1	c.-646G>T		5_prime_UTR	Exon 1 of 5	ENSP00000461223.1	O95947-2
	TBX6	ENST00000395224.7	TSL:1 MANE Select	c.-49+34G>T		intron	N/A	ENSP00000378650.2	O95947-1
	TBX6	ENST00000931584.1		c.-646G>T		5_prime_UTR	Exon 1 of 8	ENSP00000601643.1

Frequencies

GnomAD3 genomes AF: 0.415 AC: 63030 AN: 152034 Hom.: 13469 Cov.: 33

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.421

GnomAD4 exome AF: 0.348 AC: 64 AN: 184 Hom.: 12 Cov.: 0 AF XY: 0.358 AC XY: 48 AN XY: 134

African (AFR) AF: 0.200 AC: 2 AN: 10

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.328 AC: 19 AN: 58

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.373 AC: 38 AN: 102

Other (OTH) AF: 0.375 AC: 3 AN: 8

GnomAD4 genome AF: 0.415 AC: 63089 AN: 152152 Hom.: 13496 Cov.: 33 AF XY: 0.421 AC XY: 31330 AN XY: 74374

African (AFR) AF: 0.347 AC: 14414 AN: 41526

American (AMR) AF: 0.482 AC: 7372 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1603 AN: 3468

East Asian (EAS) AF: 0.571 AC: 2948 AN: 5160

South Asian (SAS) AF: 0.486 AC: 2343 AN: 4820

European-Finnish (FIN) AF: 0.483 AC: 5116 AN: 10590

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.411 AC: 27937 AN: 67976

Other (OTH) AF: 0.426 AC: 901 AN: 2114

Alfa AF: 0.415 Hom.: 7897

Bravo AF: 0.415

Asia WGS AF: 0.582 AC: 2021 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	1	-	Spondylocostal dysostosis 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.5
DANN	Benign	0.64
PhyloP100		-0.84
PromoterAI		0.070	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs3809627; hg19: chr16-30103160;