chr12-114408030-C-A

Variant names:

• chr12-114408030-C-A
• rs186472610
• ENST00000310346.8:c.-255G>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000192.3(TBX5):​c.-255G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 985,440 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: TBX5 NM_000192.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97
• Publications: 1 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-AS1 (HGNC:27402): (TBX5 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000991 (151/152324) while in subpopulation NFE AF = 0.0015 (102/68034). AF 95% confidence interval is 0.00126. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 151 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000192.3. 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_000192.3		c.-255G>T		5_prime_UTR	Exon 1 of 9	NP_000183.2	Q99593-1
	TBX5	NM_080717.4		c.-220G>T		upstream_gene	N/A	NP_542448.1	Q99593-3
	TBX5-AS1	NR_038440.1		n.-165C>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	ENST00000310346.8	TSL:1	c.-255G>T		5_prime_UTR	Exon 1 of 9	ENSP00000309913.4	Q99593-1
	TBX5	ENST00000349716.9	TSL:1	c.-220G>T		5_prime_UTR	Exon 1 of 8	ENSP00000337723.5	Q99593-3
	TBX5	ENST00000860921.1		c.-250G>T		5_prime_UTR	Exon 1 of 9	ENSP00000530980.1

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00202 AC: 1687 AN: 833116 Hom.: 1 Cov.: 29 AF XY: 0.00214 AC XY: 824 AN XY: 384722

African (AFR) AF: 0.000127 AC: 2 AN: 15786

American (AMR) AF: 0.00 AC: 0 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5152

East Asian (EAS) AF: 0.00 AC: 0 AN: 3632

South Asian (SAS) AF: 0.000790 AC: 13 AN: 16460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 276

Middle Eastern (MID) AF: 0.000617 AC: 1 AN: 1620

European-Non Finnish (NFE) AF: 0.00214 AC: 1628 AN: 761908

Other (OTH) AF: 0.00158 AC: 43 AN: 27298

GnomAD4 genome AF: 0.000991 AC: 151 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74482

African (AFR) AF: 0.000313 AC: 13 AN: 41566

American (AMR) AF: 0.000981 AC: 15 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000556 Hom.: 0

Bravo AF: 0.00100

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.94
PhyloP100		2.0
PromoterAI		-0.0033	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs186472610; hg19: chr12-114845835;