NM_181486.4:c.*1385delT

Variant names:

• chr12-114354146-GA-G
• rs35534655
• NM_181486.4:c.*1385delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_181486.4(TBX5):​c.*1385delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.79 (47525 hom., cov: 0)
  • Exomes 𝑓: 0.76 (123 hom.)
• Consequence: TBX5 NM_181486.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.722
• Publications: 2 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P, PanelApp Australia, Orphanet
• heart conduction disease

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 12-114354146-GA-G is Benign according to our data. Variant chr12-114354146-GA-G is described in ClinVar as Benign. ClinVar VariationId is 307269.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

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.*1385delT		3_prime_UTR	Exon 9 of 9	NP_852259.1	Q99593-1
	TBX5	NM_000192.3		c.*1385delT		3_prime_UTR	Exon 9 of 9	NP_000183.2	Q99593-1
	TBX5	NM_080717.4		c.*1385delT		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.*1385delT		3_prime_UTR	Exon 9 of 9	ENSP00000384152.3	Q99593-1
	TBX5	ENST00000310346.8	TSL:1	c.*1385delT		3_prime_UTR	Exon 9 of 9	ENSP00000309913.4	Q99593-1
	TBX5	ENST00000349716.9	TSL:1	c.*1385delT		3_prime_UTR	Exon 8 of 8	ENSP00000337723.5	Q99593-3

Frequencies

GnomAD3 genomes AF: 0.794 AC: 119394 AN: 150330 Hom.: 47491 Cov.: 0

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.848

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.771

Gnomad FIN AF: 0.780

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.786

GnomAD4 exome AF: 0.762 AC: 329 AN: 432 Hom.: 123 Cov.: 0 AF XY: 0.765 AC XY: 199 AN XY: 260

African (AFR) AC: 0 AN: 0

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: 0.763 AC: 325 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.794 AC: 119470 AN: 150436 Hom.: 47525 Cov.: 0 AF XY: 0.792 AC XY: 58088 AN XY: 73348

African (AFR) AF: 0.779 AC: 31881 AN: 40906

American (AMR) AF: 0.705 AC: 10620 AN: 15066

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2712 AN: 3458

East Asian (EAS) AF: 0.910 AC: 4667 AN: 5130

South Asian (SAS) AF: 0.771 AC: 3658 AN: 4744

European-Finnish (FIN) AF: 0.780 AC: 7940 AN: 10182

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.818 AC: 55346 AN: 67664

Other (OTH) AF: 0.787 AC: 1641 AN: 2084

Alfa AF: 0.700 Hom.: 1342

ClinVar

ClinVar submissions

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
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs35534655; hg19: chr12-114791951; COSMIC: COSV59858217; COSMIC: COSV59858217;