12-114397623-G-T

Variant names:

• chr12-114397623-G-T
• rs1895602
• NM_181486.4:c.510+950C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181486.4(TBX5):​c.510+950C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 151,950 control chromosomes in the GnomAD database, including 13,558 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (13558 hom., cov: 33)
• Consequence: TBX5 NM_181486.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• Publications: 7 publications found

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]

TBX5 Gene-Disease associations (from GenCC):

• Holt-Oram syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• heart conduction disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ENSG00000297256 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181486.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	NM_181486.4	MANE Select	c.510+950C>A		intron	N/A	NP_852259.1
	TBX5	NM_000192.3		c.510+950C>A		intron	N/A	NP_000183.2
	TBX5	NM_080717.4		c.360+950C>A		intron	N/A	NP_542448.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	ENST00000405440.7	TSL:1 MANE Select	c.510+950C>A		intron	N/A	ENSP00000384152.3
	TBX5	ENST00000310346.8	TSL:1	c.510+950C>A		intron	N/A	ENSP00000309913.4
	TBX5	ENST00000349716.9	TSL:1	c.360+950C>A		intron	N/A	ENSP00000337723.5

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60455 AN: 151832 Hom.: 13550 Cov.: 33

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.412

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.398 AC: 60498 AN: 151950 Hom.: 13558 Cov.: 33 AF XY: 0.408 AC XY: 30330 AN XY: 74270

African (AFR) AF: 0.191 AC: 7921 AN: 41424

American (AMR) AF: 0.575 AC: 8786 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 1664 AN: 3472

East Asian (EAS) AF: 0.336 AC: 1731 AN: 5156

South Asian (SAS) AF: 0.557 AC: 2685 AN: 4820

European-Finnish (FIN) AF: 0.553 AC: 5842 AN: 10572

Middle Eastern (MID) AF: 0.442 AC: 129 AN: 292

European-Non Finnish (NFE) AF: 0.450 AC: 30549 AN: 67926

Other (OTH) AF: 0.414 AC: 874 AN: 2112

Alfa AF: 0.438 Hom.: 24820

Bravo AF: 0.387

Asia WGS AF: 0.452 AC: 1568 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.1
DANN	Benign	0.48
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1895602; hg19: chr12-114835428;