12-114366343-G-T

Position:

• chr12-114366343-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The ENST00000405440.7(TBX5):​c.804C>A​(p.Ala268=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A268A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 ENST00000405440.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.804C>A	p.Ala268=	synonymous_variant	8/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.804C>A	p.Ala268=	synonymous_variant	8/9		NP_000183.2
TBX5	NM_080717.4	c.654C>A	p.Ala218=	synonymous_variant	7/8		NP_542448.1
TBX5	XM_017019912.2	c.852C>A	p.Ala284=	synonymous_variant	8/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.804C>A	p.Ala268=	synonymous_variant	8/9	1	NM_181486.4	ENSP00000384152	P1
TBX5	ENST00000310346.8	c.804C>A	p.Ala268=	synonymous_variant	8/9	1		ENSP00000309913	P1
TBX5	ENST00000349716.9	c.654C>A	p.Ala218=	synonymous_variant	7/8	1		ENSP00000337723
TBX5	ENST00000526441.1	c.804C>A	p.Ala268=	synonymous_variant	7/7	1		ENSP00000433292

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
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.7
DANN	Benign	0.73

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: rs35110399; hg19: chr12-114804148; COSMIC: COSV100090560;