12-114366366-T-C

Position:

• chr12-114366366-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000405440.7(TBX5):​c.781A>G​(p.Ser261Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBX5 ENST00000405440.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.781A>G	p.Ser261Gly	missense_variant	8/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.781A>G	p.Ser261Gly	missense_variant	8/9		NP_000183.2
TBX5	NM_080717.4	c.631A>G	p.Ser211Gly	missense_variant	7/8		NP_542448.1
TBX5	XM_017019912.2	c.829A>G	p.Ser277Gly	missense_variant	8/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.781A>G	p.Ser261Gly	missense_variant	8/9	1	NM_181486.4	ENSP00000384152	P1
TBX5	ENST00000310346.8	c.781A>G	p.Ser261Gly	missense_variant	8/9	1		ENSP00000309913	P1
TBX5	ENST00000349716.9	c.631A>G	p.Ser211Gly	missense_variant	7/8	1		ENSP00000337723
TBX5	ENST00000526441.1	c.781A>G	p.Ser261Gly	missense_variant	7/7	1		ENSP00000433292

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;.;T;T
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.3	.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.048	D;D;D;D
Polyphen		1.0, 0.91	.;D;D;P
Vest4		0.73
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		0.82
MPC		0.86
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.44
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs377625550; hg19: chr12-114804171;