rs140666098

Positions:

• chr16-30088717-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004608.4(TBX6):​c.744C>T​(p.Ser248Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,614,140 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: TBX6 NM_004608.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -8.99

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 16-30088717-G-A is Benign according to our data. Variant chr16-30088717-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00126 (192/152278) while in subpopulation SAS AF= 0.00374 (18/4818). AF 95% confidence interval is 0.00241. There are 0 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX6	NM_004608.4	c.744C>T	p.Ser248Ser	synonymous_variant	5/9	ENST00000395224.7	NP_004599.2
TBX6	XM_011545926.4	c.744C>T	p.Ser248Ser	synonymous_variant	5/9		XP_011544228.1
TBX6	XM_047434551.1	c.744C>T	p.Ser248Ser	synonymous_variant	4/8		XP_047290507.1
TBX6	XR_007064904.1	n.867C>T		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX6	ENST00000395224.7	c.744C>T	p.Ser248Ser	synonymous_variant	5/9	1	NM_004608.4	ENSP00000378650.2
TBX6	ENST00000279386.6	c.744C>T	p.Ser248Ser	synonymous_variant	4/8	1		ENSP00000279386.2
TBX6	ENST00000553607.1	c.744C>T	p.Ser248Ser	synonymous_variant	4/5	1		ENSP00000461223.1
TBX6	ENST00000567664.5	n.744C>T		non_coding_transcript_exon_variant	4/7	5		ENSP00000460425.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00602

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00173 AC: 434 AN: 251408 Hom.: 1 AF XY: 0.00208 AC XY: 282 AN XY: 135876

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00516

Gnomad FIN exome AF: 0.00444

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00144 AC: 2112 AN: 1461862 Hom.: 5 Cov.: 31 AF XY: 0.00163 AC XY: 1189 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00576

Gnomad4 FIN exome AF: 0.00369

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74456

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00374

Gnomad4 FIN AF: 0.00602

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00137 Hom.: 0

Bravo AF: 0.000638

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	TBX6: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.42
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140666098; hg19: chr16-30100038;