rs104894378

Positions:

• chr12-114385521-C-G
• chr12-114385521-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The ENST00000405440.7(TBX5):​c.710G>C​(p.Arg237Pro) 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R237Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 ENST00000405440.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.48

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in ENST00000405440.7
• 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 ClinVar as [Likely_pathogenic]. Clinvar id is 7993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 12-114385521-C-G is Pathogenic according to our data. Variant chr12-114385521-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 372783.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.710G>C	p.Arg237Pro	missense_variant	7/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.710G>C	p.Arg237Pro	missense_variant	7/9		NP_000183.2
TBX5	NM_080717.4	c.560G>C	p.Arg187Pro	missense_variant	6/8		NP_542448.1
TBX5	XM_017019912.2	c.758G>C	p.Arg253Pro	missense_variant	7/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.710G>C	p.Arg237Pro	missense_variant	7/9	1	NM_181486.4	ENSP00000384152	P1
TBX5	ENST00000310346.8	c.710G>C	p.Arg237Pro	missense_variant	7/9	1		ENSP00000309913	P1
TBX5	ENST00000349716.9	c.560G>C	p.Arg187Pro	missense_variant	6/8	1		ENSP00000337723
TBX5	ENST00000526441.1	c.710G>C	p.Arg237Pro	missense_variant	6/7	1		ENSP00000433292

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2016

The R237P variant in the TBX5 gene has been reported previously in a father and child with Holt-Oram syndrome (Boogerd et al., 2010). The R237P variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R237P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies demonstrate that R237P-TBX5 has decreased DNA-binding activity and diminished interaction with NKX2-5 (Boogerd et al., 2010). A missense variant at the same residue (R237Q) has been reported in association with Holt-Oram Syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R237P as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.1	D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.96
MutPred		0.85		.;Gain of ubiquitination at K234 (P = 0.041);Gain of ubiquitination at K234 (P = 0.041);Gain of ubiquitination at K234 (P = 0.041);
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.93

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: rs104894378; hg19: chr12-114823326;