12-114366343-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_181486.4(TBX5):ā€‹c.804C>Gā€‹(p.Ala268Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000262 in 1,614,062 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0013 ( 0 hom., cov: 32)
Exomes š‘“: 0.00015 ( 2 hom. )

Consequence

TBX5
NM_181486.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.08
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
Variant 12-114366343-G-C is Benign according to our data. Variant chr12-114366343-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 519262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=1.08 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00133 (203/152172) while in subpopulation AFR AF= 0.00453 (188/41516). AF 95% confidence interval is 0.004. There are 0 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 203 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TBX5NM_181486.4 linkc.804C>G p.Ala268Ala synonymous_variant 8/9 ENST00000405440.7 NP_852259.1 Q99593-1
TBX5NM_000192.3 linkc.804C>G p.Ala268Ala synonymous_variant 8/9 NP_000183.2 Q99593-1
TBX5NM_080717.4 linkc.654C>G p.Ala218Ala synonymous_variant 7/8 NP_542448.1 Q99593-3
TBX5XM_017019912.2 linkc.852C>G p.Ala284Ala synonymous_variant 8/9 XP_016875401.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TBX5ENST00000405440.7 linkc.804C>G p.Ala268Ala synonymous_variant 8/91 NM_181486.4 ENSP00000384152.3 Q99593-1
TBX5ENST00000310346.8 linkc.804C>G p.Ala268Ala synonymous_variant 8/91 ENSP00000309913.4 Q99593-1
TBX5ENST00000349716.9 linkc.654C>G p.Ala218Ala synonymous_variant 7/81 ENSP00000337723.5 Q99593-3
TBX5ENST00000526441.1 linkc.804C>G p.Ala268Ala synonymous_variant 7/71 ENSP00000433292.1 Q99593-2

Frequencies

GnomAD3 genomes
AF:
0.00133
AC:
202
AN:
152054
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00452
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000786
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:
0.00
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000378
AC:
95
AN:
251356
Hom.:
0
AF XY:
0.000324
AC XY:
44
AN XY:
135858
show subpopulations
Gnomad AFR exome
AF:
0.00461
Gnomad AMR exome
AF:
0.000405
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.000150
AC:
220
AN:
1461890
Hom.:
2
Cov.:
32
AF XY:
0.000133
AC XY:
97
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00451
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000216
Gnomad4 OTH exome
AF:
0.000430
GnomAD4 genome
AF:
0.00133
AC:
203
AN:
152172
Hom.:
0
Cov.:
32
AF XY:
0.00126
AC XY:
94
AN XY:
74406
show subpopulations
Gnomad4 AFR
AF:
0.00453
Gnomad4 AMR
AF:
0.000785
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.0000901
Hom.:
0
Bravo
AF:
0.00147
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 28, 2018- -
Holt-Oram syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 18, 2019This variant is associated with the following publications: (PMID: 21637475) -
Aortic valve disease 2 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 25, 2022- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 01, 2016This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.46
CADD
Benign
8.5
DANN
Benign
0.70

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

LitVar

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

Other links and lift over

dbSNP: rs35110399; hg19: chr12-114804148; API