12-114355435-C-T

Variant names:

• chr12-114355435-C-T
• rs883079
• NM_181486.4:c.*97G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_181486.4(TBX5):​c.*97G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,452,266 control chromosomes in the GnomAD database, including 352,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34304 hom., cov: 32)
  • Exomes 𝑓: 0.69 (317962 hom.)
• Consequence: TBX5 NM_181486.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.967
• Publications: 70 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• heart conduction disease

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.02).
• BP6: Variant 12-114355435-C-T is Benign according to our data. Variant chr12-114355435-C-T is described in ClinVar as Benign. ClinVar VariationId is 307300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.72 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.*97G>A		3_prime_UTR	Exon 9 of 9	NP_852259.1
	TBX5	NM_000192.3		c.*97G>A		3_prime_UTR	Exon 9 of 9	NP_000183.2
	TBX5	NM_080717.4		c.*97G>A		3_prime_UTR	Exon 8 of 8	NP_542448.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	ENST00000405440.7	TSL:1 MANE Select	c.*97G>A		3_prime_UTR	Exon 9 of 9	ENSP00000384152.3
	TBX5	ENST00000310346.8	TSL:1	c.*97G>A		3_prime_UTR	Exon 9 of 9	ENSP00000309913.4
	TBX5	ENST00000349716.9	TSL:1	c.*97G>A		3_prime_UTR	Exon 8 of 8	ENSP00000337723.5

Frequencies

GnomAD3 genomes AF: 0.666 AC: 101189 AN: 151862 Hom.: 34283 Cov.: 32

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.647

GnomAD2 exomes AF: 0.611 AC: 100725 AN: 164920 AF XY: 0.618

Gnomad AFR exome AF: 0.667

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.452

Gnomad FIN exome AF: 0.675

Gnomad NFE exome AF: 0.721

Gnomad OTH exome AF: 0.657

GnomAD4 exome AF: 0.694 AC: 901902 AN: 1300284 Hom.: 317962 Cov.: 20 AF XY: 0.690 AC XY: 447237 AN XY: 648084

African (AFR) AF: 0.668 AC: 20020 AN: 29968

American (AMR) AF: 0.422 AC: 15393 AN: 36450

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 15004 AN: 24610

East Asian (EAS) AF: 0.441 AC: 16093 AN: 36516

South Asian (SAS) AF: 0.550 AC: 42595 AN: 77458

European-Finnish (FIN) AF: 0.684 AC: 31821 AN: 46510

Middle Eastern (MID) AF: 0.639 AC: 3190 AN: 4990

European-Non Finnish (NFE) AF: 0.729 AC: 720601 AN: 988842

Other (OTH) AF: 0.677 AC: 37185 AN: 54940

GnomAD4 genome AF: 0.666 AC: 101249 AN: 151982 Hom.: 34304 Cov.: 32 AF XY: 0.659 AC XY: 48937 AN XY: 74278

African (AFR) AF: 0.665 AC: 27560 AN: 41426

American (AMR) AF: 0.536 AC: 8182 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2096 AN: 3470

East Asian (EAS) AF: 0.424 AC: 2184 AN: 5156

South Asian (SAS) AF: 0.523 AC: 2517 AN: 4810

European-Finnish (FIN) AF: 0.672 AC: 7104 AN: 10564

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.726 AC: 49333 AN: 67968

Other (OTH) AF: 0.643 AC: 1359 AN: 2114

Alfa AF: 0.691 Hom.: 156063

Bravo AF: 0.654

Asia WGS AF: 0.465 AC: 1619 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.4
DANN	Benign	0.85
PhyloP100		-0.97
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: rs883079; hg19: chr12-114793240;