rs112565029

Variant names:

• chr16-30091070-G-A
• rs112565029
• NM_004608.4:c.118+6C>T

Variant summary

Our verdict is Benign. The variant received -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 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.0003351
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.68
• Publications: 3 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 -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 VariationId is 259447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3456 Unknown,AD,SD gene.

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.118+6C>T		splice_region intron	N/A	NP_004599.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX6	ENST00000395224.7	TSL:1 MANE Select	c.118+6C>T		splice_region intron	N/A	ENSP00000378650.2
	TBX6	ENST00000279386.6	TSL:1	c.118+6C>T		splice_region intron	N/A	ENSP00000279386.2
	TBX6	ENST00000553607.1	TSL:1	c.118+6C>T		splice_region intron	N/A	ENSP00000461223.1

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

GnomAD2 exomes AF: 0.0225 AC: 4368 AN: 194372 AF XY: 0.0219

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 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

African (AFR) AF: 0.00437 AC: 145 AN: 33158

American (AMR) AF: 0.00945 AC: 364 AN: 38526

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 309 AN: 25436

East Asian (EAS) AF: 0.00 AC: 0 AN: 38640

South Asian (SAS) AF: 0.00179 AC: 148 AN: 82796

European-Finnish (FIN) AF: 0.0441 AC: 2258 AN: 51194

Middle Eastern (MID) AF: 0.00473 AC: 27 AN: 5708

European-Non Finnish (NFE) AF: 0.0341 AC: 37425 AN: 1097530

Other (OTH) AF: 0.0230 AC: 1364 AN: 59342

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

African (AFR) AF: 0.00522 AC: 217 AN: 41574

American (AMR) AF: 0.0153 AC: 235 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4830

European-Finnish (FIN) AF: 0.0509 AC: 541 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0348 AC: 2365 AN: 67998

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.0289 Hom.: 27

Bravo AF: 0.0193

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	17
DANN	Benign	0.88
PhyloP100		3.7
PromoterAI		0.13	Neutral
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs112565029; hg19: chr16-30102391;