12-114364333-A-G

Variant names:

• chr12-114364333-A-G
• rs1895585
• NM_181486.4:c.982+1832T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181486.4(TBX5):​c.982+1832T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 152,046 control chromosomes in the GnomAD database, including 38,256 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.71 (38256 hom., cov: 31)
• Consequence: TBX5 NM_181486.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.754 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	NM_181486.4	MANE Select	c.982+1832T>C		intron	N/A	NP_852259.1
	TBX5	NM_000192.3		c.982+1832T>C		intron	N/A	NP_000183.2
	TBX5	NM_080717.4		c.832+1832T>C		intron	N/A	NP_542448.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	ENST00000405440.7	TSL:1 MANE Select	c.982+1832T>C		intron	N/A	ENSP00000384152.3
	TBX5	ENST00000310346.8	TSL:1	c.982+1832T>C		intron	N/A	ENSP00000309913.4
	TBX5	ENST00000349716.9	TSL:1	c.832+1832T>C		intron	N/A	ENSP00000337723.5

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107155 AN: 151928 Hom.: 38225 Cov.: 31

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.746

Gnomad OTH AF: 0.682

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.705 AC: 107229 AN: 152046 Hom.: 38256 Cov.: 31 AF XY: 0.700 AC XY: 52048 AN XY: 74322

African (AFR) AF: 0.708 AC: 29346 AN: 41468

American (AMR) AF: 0.559 AC: 8542 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2146 AN: 3470

East Asian (EAS) AF: 0.774 AC: 3989 AN: 5154

South Asian (SAS) AF: 0.588 AC: 2831 AN: 4814

European-Finnish (FIN) AF: 0.692 AC: 7302 AN: 10552

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.746 AC: 50711 AN: 67988

Other (OTH) AF: 0.681 AC: 1436 AN: 2110

Alfa AF: 0.722 Hom.: 64388

Bravo AF: 0.694

Asia WGS AF: 0.628 AC: 2185 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.16
DANN	Benign	0.47
PhyloP100		-1.3
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: rs1895585; hg19: chr12-114802138;