Variant rs104894383 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_181486.4(TBX5):c.145C>A(p.Gln49Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

TBX5
NM_181486.4 missense, splice_region

Scores

Splicing: ADA: 0.8854

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.68

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.762

PP5

Variant 12-114403754-G-T is Pathogenic according to our data. Variant chr12-114403754-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 7997.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TBX5	NM_181486.4 linkuse as main transcript	c.145C>A	p.Gln49Lys	missense_variant, splice_region_variant	2/9	ENST00000405440.7
TBX5	NM_000192.3 linkuse as main transcript	c.145C>A	p.Gln49Lys	missense_variant, splice_region_variant	2/9
TBX5	XM_017019912.2 linkuse as main transcript	c.193C>A	p.Gln65Lys	missense_variant, splice_region_variant	2/9
TBX5	NM_080717.4 linkuse as main transcript	c.-3-1834C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX5	ENST00000405440.7 linkuse as main transcript	c.145C>A	p.Gln49Lys	missense_variant, splice_region_variant	2/9	1	NM_181486.4	P1	Q99593-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Holt-Oram syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 05, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T;.

Eigen

Benign

0.068

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Uncertain

0.085

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.0

L;L;L

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.78

N;N;N

REVEL

Uncertain

0.51

Sift

Uncertain

0.024

D;D;D

Sift4G

Benign

0.24

T;T;T

Polyphen

0.038

B;B;B

Vest4

0.80

MutPred

0.62

Gain of catalytic residue at I54 (P = 0);Gain of catalytic residue at I54 (P = 0);Gain of catalytic residue at I54 (P = 0);

MVP

0.99

MPC

0.98

ClinPred

0.80

GERP RS

5.4

Varity_R

0.58

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.89

dbscSNV1_RF

Pathogenic

0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over