rs3809627

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 427809.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX6	NM_004608.4	c.-49+34G>T		intron_variant		ENST00000395224.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX6	ENST00000553607.1	c.-646G>T		5_prime_UTR_variant	1/5	1
TBX6	ENST00000395224.7	c.-49+34G>T		intron_variant		1	NM_004608.4	P1

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

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.328

Gnomad4 NFE exome AF: 0.373

Gnomad4 OTH exome AF: 0.375

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

Gnomad4 AFR AF: 0.347

Gnomad4 AMR AF: 0.482

Gnomad4 ASJ AF: 0.462

Gnomad4 EAS AF: 0.571

Gnomad4 SAS AF: 0.486

Gnomad4 FIN AF: 0.483

Gnomad4 NFE AF: 0.411

Gnomad4 OTH AF: 0.426

Alfa AF: 0.409 Hom.: 3413

Bravo AF: 0.415

Asia WGS AF: 0.582 AC: 2021 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spondylocostal dysostosis 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 18, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.5
DANN	Benign	0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs3809627; hg19: chr16-30103160;