rs566107581

Variant names:

• chr12-114354572-T-C
• rs566107581
• NM_181486.4:c.*960A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_181486.4(TBX5):​c.*960A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 152,238 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBX5 NM_181486.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0500
• Publications: 0 publications found

Genes affected

TBX5 (HGNC:11604): (T-box transcription factor 5) 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. This gene is closely linked to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12. The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

TBX5 Gene-Disease associations (from GenCC):

• Holt-Oram syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• heart conduction disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-114354572-T-C is Benign according to our data. Variant chr12-114354572-T-C is described in ClinVar as Benign. ClinVar VariationId is 307276.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000466 (71/152238) while in subpopulation SAS AF = 0.00684 (33/4822). AF 95% confidence interval is 0.00501. There are 1 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 71 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181486.4. 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
	TBX5	NM_181486.4	MANE Select	c.*960A>G		3_prime_UTR	Exon 9 of 9	NP_852259.1	Q99593-1
	TBX5	NM_000192.3		c.*960A>G		3_prime_UTR	Exon 9 of 9	NP_000183.2	Q99593-1
	TBX5	NM_080717.4		c.*960A>G		3_prime_UTR	Exon 8 of 8	NP_542448.1	Q99593-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	ENST00000405440.7	TSL:1 MANE Select	c.*960A>G		3_prime_UTR	Exon 9 of 9	ENSP00000384152.3	Q99593-1
	TBX5	ENST00000310346.8	TSL:1	c.*960A>G		3_prime_UTR	Exon 9 of 9	ENSP00000309913.4	Q99593-1
	TBX5	ENST00000349716.9	TSL:1	c.*960A>G		3_prime_UTR	Exon 8 of 8	ENSP00000337723.5	Q99593-3

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 284 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 180

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 276

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.000466 AC: 71 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74432

African (AFR) AF: 0.0000481 AC: 2 AN: 41542

American (AMR) AF: 0.000850 AC: 13 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000485 Hom.: 0

Bravo AF: 0.000382

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Holt-Oram syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.70
PhyloP100		0.050
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs566107581; hg19: chr12-114792377;