12-114385522-G-C

Variant names:

• chr12-114385522-G-C
• NM_181486.4:c.709C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_181486.4(TBX5):​c.709C>G​(p.Arg237Gly) variant causes a missense change. 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. R237Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 NM_181486.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.26

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a DNA_binding_region T-box (size 180) in uniprot entity TBX5_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_181486.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-114385521-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.709C>G	p.Arg237Gly	missense_variant	Exon 7 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.709C>G	p.Arg237Gly	missense_variant	Exon 7 of 9		NP_000183.2
TBX5	NM_080717.4	c.559C>G	p.Arg187Gly	missense_variant	Exon 6 of 8		NP_542448.1
TBX5	XM_017019912.2	c.757C>G	p.Arg253Gly	missense_variant	Exon 7 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.709C>G	p.Arg237Gly	missense_variant	Exon 7 of 9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.709C>G	p.Arg237Gly	missense_variant	Exon 7 of 9	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.559C>G	p.Arg187Gly	missense_variant	Exon 6 of 8	1		ENSP00000337723.5
TBX5	ENST00000526441.1	c.709C>G	p.Arg237Gly	missense_variant	Exon 6 of 7	1		ENSP00000433292.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;.;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	.;H;H;H
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.92
MutPred		0.77		.;Gain of catalytic residue at S239 (P = 0);Gain of catalytic residue at S239 (P = 0);Gain of catalytic residue at S239 (P = 0);
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-114823327;