12-114358479-G-T

Variant names:

• chr12-114358479-G-T
• rs10507246
• NM_181486.4:c.983-2373C>A

Variant summary

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

The NM_181486.4(TBX5):​c.983-2373C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0945 in 152,082 control chromosomes in the GnomAD database, including 821 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 0.094 (821 hom., cov: 32)
• Consequence: TBX5 NM_181486.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.158
• Publications: 7 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.983-2373C>A		intron_variant	Intron 8 of 8	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.983-2373C>A		intron_variant	Intron 8 of 8		NP_000183.2
TBX5	NM_080717.4	c.833-2373C>A		intron_variant	Intron 7 of 7		NP_542448.1
TBX5	XM_017019912.2	c.1031-2373C>A		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.983-2373C>A		intron_variant	Intron 8 of 8	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.983-2373C>A		intron_variant	Intron 8 of 8	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.833-2373C>A		intron_variant	Intron 7 of 7	1		ENSP00000337723.5

Frequencies

GnomAD3 genomes AF: 0.0946 AC: 14369 AN: 151964 Hom.: 825 Cov.: 32

Gnomad AFR AF: 0.0815

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0848

Gnomad MID AF: 0.169

Gnomad NFE AF: 0.0782

Gnomad OTH AF: 0.109

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

GnomAD4 genome AF: 0.0945 AC: 14369 AN: 152082 Hom.: 821 Cov.: 32 AF XY: 0.0964 AC XY: 7169 AN XY: 74352

African (AFR) AF: 0.0814 AC: 3379 AN: 41494

American (AMR) AF: 0.150 AC: 2295 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 607 AN: 3468

East Asian (EAS) AF: 0.137 AC: 705 AN: 5158

South Asian (SAS) AF: 0.177 AC: 849 AN: 4810

European-Finnish (FIN) AF: 0.0848 AC: 896 AN: 10570

Middle Eastern (MID) AF: 0.164 AC: 48 AN: 292

European-Non Finnish (NFE) AF: 0.0782 AC: 5316 AN: 67988

Other (OTH) AF: 0.113 AC: 237 AN: 2106

Alfa AF: 0.0885 Hom.: 2744

Bravo AF: 0.0992

Asia WGS AF: 0.180 AC: 626 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.55
PhyloP100		0.16
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: rs10507246; hg19: chr12-114796284;