Genetic Variant NM_181486.4:c.781A>C (chr12-114366366-T-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_181486.4(TBX5):c.781A>C(p.Ser261Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S261C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TBX5
NM_181486.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.67

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4 link	c.781A>C	p.Ser261Arg	missense_variant	Exon 8 of 9	ENST00000405440.7	NP_852259.1	Q99593-1
TBX5	NM_000192.3 link	c.781A>C	p.Ser261Arg	missense_variant	Exon 8 of 9		NP_000183.2	Q99593-1
TBX5	NM_080717.4 link	c.631A>C	p.Ser211Arg	missense_variant	Exon 7 of 8		NP_542448.1	Q99593-3
TBX5	XM_017019912.2 link	c.829A>C	p.Ser277Arg	missense_variant	Exon 8 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBX5	ENST00000405440.7 link	c.781A>C	p.Ser261Arg	missense_variant	Exon 8 of 9	1	NM_181486.4	ENSP00000384152.3	Q99593-1
TBX5	ENST00000310346.8 link	c.781A>C	p.Ser261Arg	missense_variant	Exon 8 of 9	1		ENSP00000309913.4	Q99593-1
TBX5	ENST00000349716.9 link	c.631A>C	p.Ser211Arg	missense_variant	Exon 7 of 8	1		ENSP00000337723.5	Q99593-3
TBX5	ENST00000526441.1 link	c.781A>C	p.Ser261Arg	missense_variant	Exon 7 of 7	1		ENSP00000433292.1	Q99593-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

.;D;D;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;.;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.79

D;D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.3

.;M;M;M

PhyloP100

7.7

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Uncertain

0.58

Sift

Benign

0.061

T;T;T;T

Sift4G

Benign

0.079

T;D;D;T

Polyphen

1.0, 0.97

.;D;D;D

Vest4

0.77

MutPred

0.34

.;Loss of phosphorylation at S261 (P = 0.0182);Loss of phosphorylation at S261 (P = 0.0182);Loss of phosphorylation at S261 (P = 0.0182);

MVP

0.77

MPC

1.9

ClinPred

0.97

GERP RS

5.6

Varity_R

0.47

gMVP

0.72

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over