12-114366311-C-G

Variant names:

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

Variant summary

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

The NM_181486.4(TBX5):​c.836G>C​(p.Arg279Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• 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>C	p.Arg279Pro	missense_variant	Exon 8 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.836G>C	p.Arg279Pro	missense_variant	Exon 8 of 9		NP_000183.2
TBX5	NM_080717.4	c.686G>C	p.Arg229Pro	missense_variant	Exon 7 of 8		NP_542448.1
TBX5	XM_017019912.2	c.884G>C	p.Arg295Pro	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>C	p.Arg279Pro	missense_variant	Exon 8 of 9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.836G>C	p.Arg279Pro	missense_variant	Exon 8 of 9	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.686G>C	p.Arg229Pro	missense_variant	Exon 7 of 8	1		ENSP00000337723.5
TBX5	ENST00000526441.1	c.836G>C	p.Arg279Pro	missense_variant	Exon 7 of 7	1		ENSP00000433292.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;T;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.8	.;L;L;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.26	N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.074	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.94, 0.86	.;P;P;P
Vest4		0.60
MutPred		0.35		.;Gain of catalytic residue at F274 (P = 0.0067);Gain of catalytic residue at F274 (P = 0.0067);Gain of catalytic residue at F274 (P = 0.0067);
MVP		0.65
MPC		0.53
ClinPred		0.91	D
GERP RS		4.7
Varity_R		0.17
gMVP		0.46

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;