rs1555226301

Positions:

• chr12-114398568-C-G
• chr12-114398568-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000405440.7(TBX5):​c.510+5G>C variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 ENST00000405440.7 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.57

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
• PP5: Variant 12-114398568-C-G is Pathogenic according to our data. Variant chr12-114398568-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 633761.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.510+5G>C		splice_donor_5th_base_variant, intron_variant		ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.510+5G>C		splice_donor_5th_base_variant, intron_variant			NP_000183.2
TBX5	NM_080717.4	c.360+5G>C		splice_donor_5th_base_variant, intron_variant			NP_542448.1
TBX5	XM_017019912.2	c.558+5G>C		splice_donor_5th_base_variant, intron_variant			XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.510+5G>C		splice_donor_5th_base_variant, intron_variant		1	NM_181486.4	ENSP00000384152	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Holt-Oram syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jun 14, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.90		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555226301; hg19: chr12-114836373;