12-114366311-C-A

Variant names:

• chr12-114366311-C-A
• rs115178276
• NM_181486.4:c.836G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_181486.4(TBX5):​c.836G>T​(p.Arg279Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R279Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBX5 NM_181486.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.64

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.836G>T	p.Arg279Leu	missense_variant	Exon 8 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.836G>T	p.Arg279Leu	missense_variant	Exon 8 of 9		NP_000183.2
TBX5	NM_080717.4	c.686G>T	p.Arg229Leu	missense_variant	Exon 7 of 8		NP_542448.1
TBX5	XM_017019912.2	c.884G>T	p.Arg295Leu	missense_variant	Exon 8 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.836G>T	p.Arg279Leu	missense_variant	Exon 8 of 9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.836G>T	p.Arg279Leu	missense_variant	Exon 8 of 9	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.686G>T	p.Arg229Leu	missense_variant	Exon 7 of 8	1		ENSP00000337723.5
TBX5	ENST00000526441.1	c.836G>T	p.Arg279Leu	missense_variant	Exon 7 of 7	1		ENSP00000433292.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

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	0.15
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;D;D;.
Eigen	Benign	0.10
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.8	.;L;L;L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.68, 0.76	.;P;P;P
Vest4		0.57
MutPred		0.41		.;Gain of catalytic residue at F274 (P = 0.0028);Gain of catalytic residue at F274 (P = 0.0028);Gain of catalytic residue at F274 (P = 0.0028);
MVP		0.54
MPC		0.30
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.12
gMVP		0.37

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

Other links and lift over

dbSNP: rs115178276; hg19: chr12-114804116; COSMIC: COSV59862731;