dbSNP rs773397553: TBX5:p.Pro14Ser (chr12-114403859-G-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_181486.4(TBX5):c.40C>T(p.Pro14Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,550 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. P14T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TBX5
NM_181486.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.79

Publications

2 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: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-114403859-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 446369.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 2 of 9	ENST00000405440.7	NP_852259.1	Q99593-1
TBX5	NM_000192.3 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 2 of 9		NP_000183.2	Q99593-1
TBX5	XM_017019912.2 link	c.88C>T	p.Pro30Ser	missense_variant	Exon 2 of 9		XP_016875401.1
TBX5	NM_080717.4 link	c.-3-1939C>T		intron_variant	Intron 1 of 7		NP_542448.1	Q99593-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 2 of 9	1	NM_181486.4	ENSP00000384152.3		Q99593-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111954

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T;.

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

.;T;T

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.79

D;D;D

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

1.0

L;L;L

PhyloP100

8.8

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.5

N;N;N

REVEL

Uncertain

0.59

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.029

D;D;T

Polyphen

0.99

D;D;D

Vest4

0.74

MutPred

0.30

Gain of catalytic residue at L10 (P = 0.0061);Gain of catalytic residue at L10 (P = 0.0061);Gain of catalytic residue at L10 (P = 0.0061);

MVP

0.92

MPC

1.7

ClinPred

0.94

GERP RS

5.3

PromoterAI

0.025

Neutral

(source)

Varity_R

0.14

gMVP

0.63

Mutation Taster

=28/72

disease causing

(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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rs773397553

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over