12-114394705-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_181486.4(TBX5):c.663+36G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,612,396 control chromosomes in the GnomAD database, including 308,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 25471 hom., cov: 31)

Exomes 𝑓: 0.62 ( 283352 hom. )

Consequence

TBX5
NM_181486.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:4

Conservation

PhyloP100: -0.956

Publications

14 publications found

Variant links:

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

TBX5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 12-114394705-C-A is Benign according to our data. Variant chr12-114394705-C-A is described in ClinVar as Benign. ClinVar VariationId is 139592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4 link	c.663+36G>T	intron_variant	Intron 6 of 8	ENST00000405440.7	NP_852259.1	Q99593-1
TBX5	NM_000192.3 link	c.663+36G>T	intron_variant	Intron 6 of 8		NP_000183.2	Q99593-1
TBX5	NM_080717.4 link	c.513+36G>T	intron_variant	Intron 5 of 7		NP_542448.1	Q99593-3
TBX5	XM_017019912.2 link	c.711+36G>T	intron_variant	Intron 6 of 8		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7 link	c.663+36G>T		intron_variant	Intron 6 of 8	1	NM_181486.4	ENSP00000384152.3		Q99593-1

Frequencies

GnomAD3 genomes

AF:

0.569

AC:

86344

AN:

151822

Hom.:

25451

Cov.:

show subpopulations

Gnomad AFR

AF:

0.424

Gnomad AMI

AF:

0.423

Gnomad AMR

AF:

0.715

Gnomad ASJ

AF:

0.618

Gnomad EAS

AF:

0.346

Gnomad SAS

AF:

0.674

Gnomad FIN

AF:

0.619

Gnomad MID

AF:

0.652

Gnomad NFE

AF:

0.624

Gnomad OTH

AF:

0.589

GnomAD2 exomes

AF:

0.619

AC:

155374

AN:

251088

AF XY:

0.622

show subpopulations

Gnomad AFR exome

AF:

0.417

Gnomad AMR exome

AF:

0.795

Gnomad ASJ exome

AF:

0.617

Gnomad EAS exome

AF:

0.337

Gnomad FIN exome

AF:

0.619

Gnomad NFE exome

AF:

0.628

Gnomad OTH exome

AF:

0.603

GnomAD4 exome

AF:

0.619

AC:

904338

AN:

1460456

Hom.:

283352

Cov.:

AF XY:

0.620

AC XY:

450819

AN XY:

726584

show subpopulations

African (AFR)

AF:

0.415

AC:

13863

AN:

33444

American (AMR)

AF:

0.782

AC:

34954

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.620

AC:

16204

AN:

26116

East Asian (EAS)

AF:

0.364

AC:

14427

AN:

39684

South Asian (SAS)

AF:

0.670

AC:

57725

AN:

86212

European-Finnish (FIN)

AF:

0.611

AC:

32525

AN:

53232

Middle Eastern (MID)

AF:

0.594

AC:

3413

AN:

5748

European-Non Finnish (NFE)

AF:

0.626

AC:

695427

AN:

1110978

Other (OTH)

AF:

0.593

AC:

35800

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

15949

31899

47848

63798

79747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18512

37024

55536

74048

92560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.569

AC:

86413

AN:

151940

Hom.:

25471

Cov.:

AF XY:

0.573

AC XY:

42549

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.424

AC:

17552

AN:

41406

American (AMR)

AF:

0.715

AC:

10927

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.618

AC:

2138

AN:

3462

East Asian (EAS)

AF:

0.347

AC:

1786

AN:

5140

South Asian (SAS)

AF:

0.674

AC:

3239

AN:

4806

European-Finnish (FIN)

AF:

0.619

AC:

6537

AN:

10568

Middle Eastern (MID)

AF:

0.660

AC:

194

AN:

294

European-Non Finnish (NFE)

AF:

0.624

AC:

42409

AN:

67964

Other (OTH)

AF:

0.589

AC:

1245

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1856

3712

5568

7424

9280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

736

1472

2208

2944

3680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.552

Hom.:

7981

Bravo

AF:

0.566

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Molecular Genetics and Enzymology, National Research Centre

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Holt-Oram syndrome

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.18

(source)

DANN

Benign

0.60

PhyloP100

-0.96

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over