rs1946295

Variant names:

• chr12-114364556-A-G
• rs1946295
• NM_181486.4:c.982+1609T>C

Variant summary

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

The NM_181486.4(TBX5):​c.982+1609T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 151,980 control chromosomes in the GnomAD database, including 37,395 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 0.70 (37395 hom., cov: 31)
• Consequence: TBX5 NM_181486.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.619
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.982+1609T>C		intron_variant	Intron 8 of 8	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.982+1609T>C		intron_variant	Intron 8 of 8		NP_000183.2
TBX5	NM_080717.4	c.832+1609T>C		intron_variant	Intron 7 of 7		NP_542448.1
TBX5	XM_017019912.2	c.1030+1609T>C		intron_variant	Intron 8 of 8		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.982+1609T>C		intron_variant	Intron 8 of 8	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.982+1609T>C		intron_variant	Intron 8 of 8	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.832+1609T>C		intron_variant	Intron 7 of 7	1		ENSP00000337723.5

Frequencies

GnomAD3 genomes AF: 0.697 AC: 105905 AN: 151862 Hom.: 37371 Cov.: 31

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.806

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.746

Gnomad OTH AF: 0.678

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

GnomAD4 genome AF: 0.697 AC: 105972 AN: 151980 Hom.: 37395 Cov.: 31 AF XY: 0.692 AC XY: 51439 AN XY: 74290

African (AFR) AF: 0.679 AC: 28134 AN: 41426

American (AMR) AF: 0.556 AC: 8487 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2146 AN: 3470

East Asian (EAS) AF: 0.774 AC: 3994 AN: 5162

South Asian (SAS) AF: 0.588 AC: 2827 AN: 4806

European-Finnish (FIN) AF: 0.692 AC: 7308 AN: 10562

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.746 AC: 50726 AN: 67968

Other (OTH) AF: 0.676 AC: 1424 AN: 2106

Alfa AF: 0.718 Hom.: 19997

Bravo AF: 0.685

Asia WGS AF: 0.625 AC: 2175 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.7
DANN	Benign	0.84
PhyloP100		0.62
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: rs1946295; hg19: chr12-114802361;