rs112565029

Positions:

• chr16-30091070-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004608.4(TBX6):​c.118+6C>T variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.0287 in 1,584,626 control chromosomes in the GnomAD database, including 780 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (45 hom., cov: 32)
  • Exomes 𝑓: 0.029 (735 hom.)
• Consequence: TBX6 NM_004608.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0003351
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.68

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-30091070-G-A is Benign according to our data. Variant chr16-30091070-G-A is described in ClinVar as [Benign]. Clinvar id is 259447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30091070-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0227 (3456/152296) while in subpopulation NFE AF= 0.0348 (2365/67998). AF 95% confidence interval is 0.0336. There are 45 homozygotes in gnomad4. There are 1715 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 45 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX6	NM_004608.4	c.118+6C>T		splice_donor_region_variant, intron_variant		ENST00000395224.7
TBX6	XM_011545926.4	c.118+6C>T		splice_donor_region_variant, intron_variant
TBX6	XM_047434551.1	c.118+6C>T		splice_donor_region_variant, intron_variant
TBX6	XR_007064904.1	n.241+6C>T		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX6	ENST00000395224.7	c.118+6C>T		splice_donor_region_variant, intron_variant		1	NM_004608.4	P1
TBX6	ENST00000279386.6	c.118+6C>T		splice_donor_region_variant, intron_variant		1		P1
TBX6	ENST00000553607.1	c.118+6C>T		splice_donor_region_variant, intron_variant		1
TBX6	ENST00000567664.5	c.118+6C>T		splice_donor_region_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3453 AN: 152180 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00523

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0509

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0348

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0225 AC: 4368 AN: 194372 Hom.: 72 AF XY: 0.0219 AC XY: 2295 AN XY: 104810

Gnomad AFR exome AF: 0.00586

Gnomad AMR exome AF: 0.00879

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00164

Gnomad FIN exome AF: 0.0465

Gnomad NFE exome AF: 0.0362

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0294 AC: 42040 AN: 1432330 Hom.: 735 Cov.: 31 AF XY: 0.0285 AC XY: 20236 AN XY: 709820

Gnomad4 AFR exome AF: 0.00437

Gnomad4 AMR exome AF: 0.00945

Gnomad4 ASJ exome AF: 0.0121

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.0441

Gnomad4 NFE exome AF: 0.0341

Gnomad4 OTH exome AF: 0.0230

GnomAD4 genome AF: 0.0227 AC: 3456 AN: 152296 Hom.: 45 Cov.: 32 AF XY: 0.0230 AC XY: 1715 AN XY: 74466

Gnomad4 AFR AF: 0.00522

Gnomad4 AMR AF: 0.0153

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0509

Gnomad4 NFE AF: 0.0348

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0289 Hom.: 27

Bravo AF: 0.0193

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	17
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.0080
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: rs112565029; hg19: chr16-30102391;