12-114355435-C-T

Variant names:

• chr12-114355435-C-T
• rs883079
• NM_181486.4:c.*97G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_181486.4(TBX5):​c.*97G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,452,266 control chromosomes in the GnomAD database, including 352,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34304 hom., cov: 32)
  • Exomes 𝑓: 0.69 (317962 hom.)
• Consequence: TBX5 NM_181486.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.967
• Publications: 70 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.02).
• BP6: Variant 12-114355435-C-T is Benign according to our data. Variant chr12-114355435-C-T is described in ClinVar as Benign. ClinVar VariationId is 307300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.*97G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.*97G>A		3_prime_UTR_variant	Exon 9 of 9		NP_000183.2
TBX5	NM_080717.4	c.*97G>A		3_prime_UTR_variant	Exon 8 of 8		NP_542448.1
TBX5	XM_017019912.2	c.*97G>A		3_prime_UTR_variant	Exon 9 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.*97G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.*97G>A		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.*97G>A		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000337723.5

Frequencies

GnomAD3 genomes AF: 0.666 AC: 101189 AN: 151862 Hom.: 34283 Cov.: 32

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.647

GnomAD2 exomes AF: 0.611 AC: 100725 AN: 164920 AF XY: 0.618

Gnomad AFR exome AF: 0.667

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.452

Gnomad FIN exome AF: 0.675

Gnomad NFE exome AF: 0.721

Gnomad OTH exome AF: 0.657

GnomAD4 exome AF: 0.694 AC: 901902 AN: 1300284 Hom.: 317962 Cov.: 20 AF XY: 0.690 AC XY: 447237 AN XY: 648084

African (AFR) AF: 0.668 AC: 20020 AN: 29968

American (AMR) AF: 0.422 AC: 15393 AN: 36450

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 15004 AN: 24610

East Asian (EAS) AF: 0.441 AC: 16093 AN: 36516

South Asian (SAS) AF: 0.550 AC: 42595 AN: 77458

European-Finnish (FIN) AF: 0.684 AC: 31821 AN: 46510

Middle Eastern (MID) AF: 0.639 AC: 3190 AN: 4990

European-Non Finnish (NFE) AF: 0.729 AC: 720601 AN: 988842

Other (OTH) AF: 0.677 AC: 37185 AN: 54940

GnomAD4 genome AF: 0.666 AC: 101249 AN: 151982 Hom.: 34304 Cov.: 32 AF XY: 0.659 AC XY: 48937 AN XY: 74278

African (AFR) AF: 0.665 AC: 27560 AN: 41426

American (AMR) AF: 0.536 AC: 8182 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2096 AN: 3470

East Asian (EAS) AF: 0.424 AC: 2184 AN: 5156

South Asian (SAS) AF: 0.523 AC: 2517 AN: 4810

European-Finnish (FIN) AF: 0.672 AC: 7104 AN: 10564

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.726 AC: 49333 AN: 67968

Other (OTH) AF: 0.643 AC: 1359 AN: 2114

Alfa AF: 0.691 Hom.: 156063

Bravo AF: 0.654

Asia WGS AF: 0.465 AC: 1619 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Holt-Oram syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.4
DANN	Benign	0.85
PhyloP100		-0.97
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: rs883079; hg19: chr12-114793240;