NM_181486.4:c.*40A>G

Variant names:

• chr12-114355492-T-C
• rs10850326
• NM_181486.4:c.*40A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181486.4(TBX5):​c.*40A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,609,080 control chromosomes in the GnomAD database, including 2,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (327 hom., cov: 33)
  • Exomes 𝑓: 0.016 (2341 hom.)
• Consequence: TBX5 NM_181486.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.30
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.016).
• BP6: Variant 12-114355492-T-C is Benign according to our data. Variant chr12-114355492-T-C is described in ClinVar as Benign. ClinVar VariationId is 255489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.335 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.*40A>G		3_prime_UTR	Exon 9 of 9	NP_852259.1
	TBX5	NM_000192.3		c.*40A>G		3_prime_UTR	Exon 9 of 9	NP_000183.2
	TBX5	NM_080717.4		c.*40A>G		3_prime_UTR	Exon 8 of 8	NP_542448.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	ENST00000405440.7	TSL:1 MANE Select	c.*40A>G		3_prime_UTR	Exon 9 of 9	ENSP00000384152.3
	TBX5	ENST00000310346.8	TSL:1	c.*40A>G		3_prime_UTR	Exon 9 of 9	ENSP00000309913.4
	TBX5	ENST00000349716.9	TSL:1	c.*40A>G		3_prime_UTR	Exon 8 of 8	ENSP00000337723.5

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2637 AN: 152216 Hom.: 328 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.0555

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00411

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0347 AC: 8526 AN: 245914 AF XY: 0.0348

Gnomad AFR exome AF: 0.00226

Gnomad AMR exome AF: 0.00467

Gnomad ASJ exome AF: 0.00251

Gnomad EAS exome AF: 0.341

Gnomad FIN exome AF: 0.00276

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0160 AC: 23289 AN: 1456748 Hom.: 2341 Cov.: 32 AF XY: 0.0169 AC XY: 12277 AN XY: 724828

African (AFR) AF: 0.00138 AC: 46 AN: 33400

American (AMR) AF: 0.00445 AC: 198 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26088

East Asian (EAS) AF: 0.324 AC: 12850 AN: 39658

South Asian (SAS) AF: 0.0511 AC: 4362 AN: 85426

European-Finnish (FIN) AF: 0.00392 AC: 209 AN: 53250

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5760

European-Non Finnish (NFE) AF: 0.00360 AC: 3988 AN: 1108470

Other (OTH) AF: 0.0249 AC: 1498 AN: 60222

GnomAD4 genome AF: 0.0173 AC: 2639 AN: 152332 Hom.: 327 Cov.: 33 AF XY: 0.0204 AC XY: 1518 AN XY: 74478

African (AFR) AF: 0.00221 AC: 92 AN: 41586

American (AMR) AF: 0.00692 AC: 106 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.349 AC: 1801 AN: 5164

South Asian (SAS) AF: 0.0564 AC: 272 AN: 4824

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00412 AC: 280 AN: 68036

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.00517 Hom.: 9

Bravo AF: 0.0183

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Holt-Oram syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.92
DANN	Benign	0.76
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: rs10850326; hg19: chr12-114793297; COSMIC: COSV59861938;