12-114362169-G-A

Variant names:

• chr12-114362169-G-A
• rs7312625
• NM_181486.4:c.982+3996C>T

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+3996C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 151,920 control chromosomes in the GnomAD database, including 38,357 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 (38357 hom., cov: 31)
• Consequence: TBX5 NM_181486.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.262
• Publications: 21 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.982+3996C>T		intron_variant	Intron 8 of 8	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.982+3996C>T		intron_variant	Intron 8 of 8		NP_000183.2
TBX5	NM_080717.4	c.832+3996C>T		intron_variant	Intron 7 of 7		NP_542448.1
TBX5	XM_017019912.2	c.1030+3996C>T		intron_variant	Intron 8 of 8		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.982+3996C>T		intron_variant	Intron 8 of 8	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.982+3996C>T		intron_variant	Intron 8 of 8	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.832+3996C>T		intron_variant	Intron 7 of 7	1		ENSP00000337723.5

Frequencies

GnomAD3 genomes AF: 0.707 AC: 107256 AN: 151802 Hom.: 38317 Cov.: 31

Gnomad AFR AF: 0.727

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.583

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.631

Gnomad NFE AF: 0.740

Gnomad OTH AF: 0.684

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

GnomAD4 genome AF: 0.707 AC: 107342 AN: 151920 Hom.: 38357 Cov.: 31 AF XY: 0.701 AC XY: 52057 AN XY: 74240

African (AFR) AF: 0.727 AC: 30133 AN: 41420

American (AMR) AF: 0.557 AC: 8504 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2154 AN: 3462

East Asian (EAS) AF: 0.775 AC: 3982 AN: 5140

South Asian (SAS) AF: 0.584 AC: 2801 AN: 4798

European-Finnish (FIN) AF: 0.677 AC: 7141 AN: 10548

Middle Eastern (MID) AF: 0.644 AC: 188 AN: 292

European-Non Finnish (NFE) AF: 0.740 AC: 50268 AN: 67970

Other (OTH) AF: 0.682 AC: 1441 AN: 2112

Alfa AF: 0.718 Hom.: 143915

Bravo AF: 0.698

Asia WGS AF: 0.624 AC: 2173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.3
DANN	Benign	0.40
PhyloP100		0.26
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: rs7312625; hg19: chr12-114799974;